Ru-Catalyzed Meta-C–H Benzylation of Arenes with Toluene

Letter pubs.acs.org/OrgLett

Ru-Catalyzed Meta-C−H Benzylation of Arenes with Toluene Derivatives Bo Li,† Sheng-Long Fang,† Dan-Ying Huang,‡ and Bing-Feng Shi*,† †

Department of Chemistry, Zhejiang University, Hangzhou 310027, China School of Chemical & Environmental Engineering, Wuyi University, Jiangmen 529020, China

‡

S Supporting Information *

ABSTRACT: The Ru-catalyzed meta-C−H benzylation of arenes bearing pyridyl, pyrimidyl, and pyrazolyl directing groups with toluene derivatives has been reported. Heptafluoroisopropyl iodide (iC3F7I) was employed as both a mild oxidant and radical initiator. This reaction showed excellent site-selectivity and tolerated a wide range of functional groups, providing a new strategy for the synthesis of various diarylmethane moieties. Scheme 1. Transition-Metal-Catalyzed Ortho- and Meta-C− H Benzylation of Arenes

T

he past decades have witnessed remarkable progress in the development of transition-metal-catalyzed directing group (DG)-assisted ortho-C−H functionalization.1 However, remote meta-selective C−H functionalization remains a major challenge.2 At the outset, specific substrates with steric and/or electronic effects have been exploited to realize meta-selective C−B and C−C bond formations.3−5 A series of well-defined U-shaped templates have been developed to assist metaselective C−H functionalization by Yu,6 Tan,7 Maiti,8 and others.9 Meanwhile, meta-selective C−H functionalization strategies mediated by norbornene10 or induced by a traceless carboxylic acid11 have also been discovered. Very recently, another efficient method using commonly used ortho-DG and the cheap metal Ru catalyst, which was enabled by orthocycloruthenation and subsequent electrophilic aromatic substitution, has been discovered by Frost,12 Ackermann,13 and others.14 However, this unique strategy has only been applied to limited types of meta-C−H functionalization reactions. Diarylmethanes are an important class of structural motifs that are present in various biologically important compounds. Traditional methods for its synthesis were mainly dependent on acid-catalyzed electrophilic aromatic benzylation reactions.15 Unfortunately, these valuable processes generally suffer from the restriction to electron-rich arenes and intolerance of diverse functional groups. Recently, transitionmetal-catalyzed C−H benzylation has become an efficient alternative for the straightforward formation of diarylmethane derivatives.16 However, these approaches were only limited to ortho-selective benzylation (Scheme 1a). Therefore, a significantly more appropriate strategy for meta-selective C− H benzylation of arenes is highly desirable. Herein, we report the first Ru-catalyzed meta-benzylation for the synthesis of diarylmethane derivatives. Notably, heptafluoroisopropyl iodide (iC3F7I) was identified as both a mild oxidant and a radical initiator (Scheme 1b).17 © 2017 American Chemical Society

Inspired by the elegant work of Ru-catalyzed meta-selective sulfonation, alkylation, bromination, and nitration reactions,12−14 we have proposed a similar regioselective approach to access meta-benzylated arenes. As depicted in Scheme 1b, starting from arene substrate, an arylruthenium intermediate could be formed via a plausible C−H ortho ruthenation process. The Ru−C σ bond of the arylruthenium intermediate could induce a strong para-directing effect.18 Then addition of electrophilic benzylation reagent will thus result in the metabenzylated product. We began our investigation by screening radical initiators in the presence of catalytic [Ru(p-cymene)Cl2]2 using 2phenylpyridine (1a) as the model substrate in toluene. Initial results showed that common radical initiators such as AIBN, potassium persulfate (K2S2O8), and dibenzoyl peroxide (BPO) Received: May 19, 2017 Published: July 19, 2017 3950

DOI: 10.1021/acs.orglett.7b01529 Org. Lett. 2017, 19, 3950−3953

Letter

Organic Letters Table 1. Optimization of the Reaction Conditions

a1

entry

initiator

1 2 3 4 5 6 7 8 9 10 11b

AIBN K2S2O8 BPO DTBP i C3F7I i C3F7I i C3F7I i C3F7I i C3F7I i C3F7I i C3F7I

additives (equiv)

solvent toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene/H2O = 4:1 toluene/H2O = 9:1

Na2CO3 (2.0) K2CO3 (2.0) KH2PO4 (2.0) PhCHO (0.5), Na2CO3 (2.0) 4-ClPhCHO (0.5), Na2CO3 (2.0) 4-ClPhCHO (0.5), Na2CO3 (2.0)

T (°C) 130 130 130 130 130 130 130 130 130 140 140

yielda (%) 0 0 0 15 25 30 0 0 40 (m/d = 3.6:1) 50 (m/d = 3.7:1) 65c (m/d = 2.5:1)

H NMR yield using CH2Br2 as the internal standard. Data in parentheses are the ratios of mono- to dibenzylation products. b48 h. cIsolated yield.

Scheme 2. Substrate Scope of Meta-Benzylation with Toluenea

gave no conversion to the desired meta-benzylation product 2a (Table 1, entries1−3). Investigations of other radical initiators indicated that heptafluoroisopropyl iodide (iC3F7I)17 performed better than di-tert-butyl peroxide (DTBP), affording the desired product in 25% yield (entry 5). Meanwhile, different additives were also examined. Na2CO3 was found to be the most optimal base and increased the yield to 30% (entries 6−8). Benzaldehyde has been proved to be an effective additive in Cu-catalyzed C2-benzylation of indoles.16f Therefore, we tried the use of benzaldehyde and Na2CO3 as additives and found that the yield was improved to 40% (entry 9, m/d = 3.6:1). To our delight, the yield could be increased to 65% (entry 11, m/d = 2.5:1) when the reaction was conducted in H2O/toluene (9:1) at 140 °C in the presence of p-chlorobenzaldehyde/Na2CO3 as additives. 2Phenylpyridine (1a) was recovered with good mass balance. We first examined the scope of the meta-benzylation reaction with toluene as coupling partner after the optimized reaction conditions were established (Scheme 2). A variety of arylpyridines proceeded smoothly under identical conditions and provided the corresponding meta-benzylated products in moderate to good yields. When there is no substituent on the arene ring or a methyl substituent at the para-position, a mixture of isolable mono- and dibenzylated products was obtained with monobenzylated products generated predominantly. However, the benzylation of p-OMe substituted arylpyridine gave monobenzylated product 2e exclusively. For meta-chloro substituted arylpyridine (1c), poor reactivity was obtained mainly due to the electronic effect. Notably, the reaction of 2-(naphthalen-2-yl)pyridine occurred smoothly, affording the desired product 2f in 63% yield. In addition, arylpyridine substrates bearing methyl or chloro on the pyridine moiety were also tolerated (2g−h, 42%−60%). Furthermore, other N-heterocycles, such as pyrimidine and pyrazole, can also act as efficient DGs (1i−l). As shown in Scheme 3, this protocol could also be applied to a range of toluene derivatives, such as ethylbenzene, oxylene, o-chlorotoluene, m-xylene and m-chlorotoluene, affording the desired products in moderate to good yields with excellent regioselectivity. Unfortunately, toluene derivatives bearing strong electron-withdrawing and electron-

a

Isolated yields. Data in parentheses are the ratios of mono- to dibenzylation products.

donating groups proved to be less successful under the standard conditions. 2-Phenylpyridine reacted well with ethylbenzene to give 3a as a single product. Meanwhile, meta-benzylated products 3i and 3j were afforded in high yields (71% and 63%) when 2-(naphthalen-2-yl)pyridine was utilized as substrate. It is worth noting that substituted arenes bearing pyrimidine (2k−n) participated in the reaction slightly better than arylpyridine substrates probably because the former are more favorable for the generation of orthometallic intermediate. Finally, the meta-benzylation structure was unambiguously confirmed by single-crystal X-ray analysis of 3n. 3951

DOI: 10.1021/acs.orglett.7b01529 Org. Lett. 2017, 19, 3950−3953

Letter

Organic Letters Scheme 3. Substrate Scope of Meta-Benzylation with Toluene Derivativesa

Scheme 4. Preliminary Mechanistic Studies

Scheme 5. Proposed Reaction Mechanism

a

Isolated yields. Data in parentheses are the ratios of mono- to dibenzylation products.

To gain greater insight into the mechanism of the metabenzylation reactions, preliminary mechanistic experiments were also performed. First, the reaction was totally shut down when the reaction was performed in the presence of radical scavengers, such as TEMPO and BHT, indicating that a radical process might be involved (Scheme 4a). Second, we also investigated the internal H/D exchange experiment of the isotopically labeled substrates (Scheme 4b). When [D5]-1a was treated with toluene/H2O under the standard reaction conditions, benzylated products [Dn]-2a and [Dn]-2a′ were obtained with a significant ortho-D/H exchange. This result clearly indicated that C−H ortho-ruthenation process was reversible under the reaction conditions. Finally, to further probe the C−H activation process, the kinetic isotope effect was conducted by using an equimolar mixture of 1a and [D5]1a. The small value of KIE (kH/kD = 1.1) suggested that C− H bond cleavage may not be involved in the rate-limiting step (Scheme 4c). On the basis of the experimental observations above and earlier literature precedents,12−14,18 a plausible mechanism for this meta-selective benzylation is proposed in Scheme 5. The arylruthenium intermediate A is first formed from substrate 1a via a reversible ortho-C−H ruthenation process. Meanwhile, a perfluoroalkyl radical is produced through base-promoted single-electron transfer (SET) process of Rf−I.18 Then the abstraction of a hydrogen atom from toluene will generate a

benzyl radical. Subsequent electrophilic attack to the paraposition of the Ru−CAr σ-bond occurs to form intermediate B. Base-promoted SET reaction of perfluoroalkyl iodide with intermediate B followed by deprotonation delivers the metabenzylated aryl-Ru intermediate C with the generation of an Rf radical. Finally, proto-demetalation releases the desired meta-benzylated product 2a and regenerates the active Ru(II)L2 species for the next catalytic cycle. In summary, we have developed the first example of metaselective benzylation of arenes via directed ortho-C−H ruthenation followed by subsequent electrophilic aromatic substitution with benzyl radical that was generated from toluene derivatives. This protocol showed excellent siteselectivity with broad scope of 2-aryl N-aromatics and coupling partners, providing a useful synthetic strategy for the preparation of diarylmethane moieties. Heptafluoroisopropyl iodide was used as a mild oxidant and radical initiator.

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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.7b01529. 3952

DOI: 10.1021/acs.orglett.7b01529 Org. Lett. 2017, 19, 3950−3953

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Organic Letters

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Experimental details and spectral data for all new compounds (PDF) X-ray data for compound 3n (CIF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Bing-Feng Shi: 0000-0003-0375-955X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the NSFC (21422206, 21572201), the National Basic Research Program of China (2015CB856600), and Zhejiang Provincial NSFC (LR17B020001) is gratefully acknowledged.

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DOI: 10.1021/acs.orglett.7b01529 Org. Lett. 2017, 19, 3950−3953