Article Cite This: J. Org. Chem. 2018, 83, 6444−6453
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Ruthenium(II)-Catalyzed Positional Selective C−H Oxygenation of N‑Aryl-2-pyrimidines Tanumay Sarkar, Sourav Pradhan, and Tharmalingam Punniyamurthy* Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India
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ABSTRACT: Efficient Ru-catalyzed regioselective C−H oxygenation of N-aryl-2-pyrimidines is described with aryl carboxylic acids in the presence of AgSbF6 as an additive and Ag2CO3 as an oxidant. The reaction can be extended to alkyl, heteroaryl, and α,β-unsaturated carboxylic acids. The regioselectivity, broad substrate scope, and functional group tolerance are the significant practical advantages.
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INTRODUCTION Transition-metal-catalyzed directed C−H bond functionalization has emerged as a reliable synthetic tool to revolutionize the development of versatile carbogenic scaffolds, owing to the proximity-driven reactivity and selectivity that is aided by a chelating group.1 In this regard, the direct C−H oxygenation2 forms a very integral constituent of C−H functionalization, due to the prevalence of C−O bonds in pharmaceuticals, agrochemicals, and material science.3 In 2004, Sanford and coworkers reported an oxime-directed Pd-catalyzed acetoxylation of C−H bonds using PhI(OAc)2 as an acylating agent,2a and Yu and co-workers demonstrated an oxazoline-directed Pdcatalyzed acetoxylation of a methyl C−H bond utilizing acid anhydride as an acyl source.2b Several studies on oxygenation of C−H bonds have been subsequently reported employing Pdand Cu-based catalytic systems with PhI(OAc)2,4 anhydride,5b,6b tert-butyl peroxyacetate,6c acid halide,6d and sodium carboxylate6e as a carboxyl source (Scheme 1a). However, the direct oxygenation of C(sp2)−H bonds with aryl carboxylic acid as an acyl source is limited, and oxazoline-,2b carboxamide-,7b sulfoximine-,7e pyridyl-,7d,g triazole-,7c and anilide7a-based directing groups are studied utilizing Pd-, Rh-, Ru-, Cu-, and Co-based catalytic systems (Scheme 1b). This strategy is attractive as it is atom economical and can lead to diverse ester scaffolds. Being a recurring moiety in bioactive molecules,8 a pyrimidine-based σ-coordinating group is employed as the directing group for C−H functionalization.9 In continuation of our studies on directed C−H functionalization,10 we report an efficient Ru-catalyzed11,12 ortho-selective oxygenation of N-aryl2-pyrimidines with benzoic acids (Scheme 1c). The reaction can be extended to alkyl, heteroaryl, and α,β-unsaturated carboxylic acids to furnish the respective esters in high yields. The reaction is scalable, and the broad substrate scope and functional group diversity are important practical features. © 2018 American Chemical Society
Scheme 1. Methods for Directed Regioselective C−H Oxygenation of Arenes
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RESULTS AND DISCUSSION Our optimization studies commenced using N-phenylpyrimidin-2-amine 1a and 4-chlorobenzoic acid 2i as the model substrates with [RuCl2(p-cymene)]2 as a catalyst in the presence of oxidants and additives (Table 1). To our delight, Received: March 21, 2018 Published: May 15, 2018 6444
DOI: 10.1021/acs.joc.8b00714 J. Org. Chem. 2018, 83, 6444−6453
Article
The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditionsa
entry
additive
oxidant
solvent
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
AgOTf AgBF4 KPF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6
Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Cu(OAc)2 K2S2O8 AgOAc Ag2O Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3
(CH2Cl)2 (CH2Cl)2 (CH2Cl)2 (CH2Cl)2 (CH2Cl)2 (CH2Cl)2 (CH2Cl)2 (CH2Cl)2 1,4-dioxane THF MeOH DMF (CH2Cl)2 (CH2Cl)2 (CH2Cl)2 (CH2Cl)2 (CH2Cl)2 (CH2Cl)2 (CH2Cl)2
39 25 43 72 0 27 21 12 59 64 23 47 0c 18d 0e 0f 0g 0 0
Ag2CO3
yields. Further, 3,4-dimethyl-substituted benzoic acid 2o and 1naphthoic acid 2p reacted to give the oxygenated products 3o and 3p in 63 and 64% yields, respectively. Interestingly, these reaction conditions can be extended to the coupling of alkyl carboxylic acids. For example, acetic acid 2q, propionic acid 2r, pivalic acid 2s, and the sterically hindered 1-adamantane carboxylic acid 2t can be reacted to produce esters 3q−t in 62− 73% yields. Furthermore, 2-phenylacetic acid 2u, 2-(4methoxyphenyl)acetic acid 2v, and 1-naphthylacetic acid 2w efficiently participated in directed C−H oxygenation to convey the corresponding esters 3u−w in 63−67% yields. The scope of the procedure was further investigated for the reaction of heteroaryl and α,β-unsaturated carboxylic acids (Scheme 3). The reaction of 2-thiophenyl 2x and 2-furanyl 2y carboxylic acids readily occurred to produce the esters 3x and 3y in 62 and 65% yields, respectively. However, 2-picolinic acid 2z was an unsuccessful substrate, which may be due to the complex formation with the Ru species. Further, the reaction of cinnamic acid 2aa occurred to furnish 3aa in 68% yield. The reaction of (E)-3-(benzo[d][1,3]dioxol-5yl)acrylic acid 2ab produced 3ab in 65% yield, whereas but-2-enoic acid 2ac gave the ester 3ac in 63% yield as a 5:1 mixture of isomers. Moreover, methacrylic acid 2ad underwent reaction to afford 3ad in 69% yield. The reaction of a series of N-aryl-2-pyrimidines 1b−l was next screened using benzoic acid 2a as a standard substrate (Scheme 4). The substrate 1b bearing substitution at the 2position of the aryl ring with a methyl group underwent reaction to give 3ae in 65% yield. The reaction of the substrates bearing the substitution at the 4-position of the aryl ring with bromo 1c, chloro 1d, fluoro 1e, iodo 1f, methyl 1g, and trifluoromethyl 1h groups produced esters 3af−ak in 52−67% yields. In addition, substrate 1i having substitution at the 3position of the aryl ring with a chloro group underwent oxygenation to furnish 3al in 71% yield. In contrast, the reactions of the substrates bearing 3-nitro 1j, 4-cyano 1k, and 4acetyl 1l groups were unsuccessful to furnish the oxygenated products. Similar results were observed with the substrates having oxazoline 1m and tetrazole 1o directing groups, which may be due to the chelation of these functional groups to the complex with Ru. However, the substrate 1n containing a pyridyl directing group can be oxygenated to provide 3aq in 63% yield. The scale-up of the reaction was investigated using 1a and 2i as the representative examples (Scheme 5). The reaction took place efficiently to provide the target oxygenated product 3i in 68% yield. These results suggest that the reaction can be scaled up to produce the oxygenated compound in good yield. To gain insight into the reaction pathway, intermolecular competitive experiments were pursued. Benzoic acid bearing electron-rich 4-methyl substituent 2k exhibited reactivity greater than that having an electron-withdrawing 4-fluoro group 2j (Scheme 6a). Similarly, the less acidic α,β-unsaturated carboxylic acid 2aa showed enhanced reactivity in comparison to the activity of the more acidic benzoic acid 2a (Scheme 6b). These results suggest that the carboxylic acids having higher pKa showed reactivity superior to that containing lower pKa, which might be attributed to the greater nucleophilicity of the conjugate base of less acidic carboxylic acids 2k and 2aa that may assist in the rapid generation of active Ru-carboxylate species. In addition, N-aryl-2-pyrimidine having an electrondonating 4-methyl group 1g was more reactive than the substrate containing an electron-withdrawing 4-fluoro function-
a
Reaction conditions: 1a (0.2 mmol), 2i (0.24 mmol), [RuCl2(pcymene)]2 (5 mol %), additive (20 mol %), oxidant (0.4 mmol), solvent (2.0 mL), 110 °C, 15 h, N2. bIsolated yield. cRuCl3 was used. d RuCl2(PPh3)3 was used. eCo(OAc)2 was used. fCu(OAc)2 was used. g Pd(OAc)2 was used.
the reaction occurred to produce the ester 3i in 39% yield when the substrates were stirred with 5 mol % of [RuCl2(pcymene)]2, 20 mol % of AgOTf, and 2 equiv of Ag2CO3 at 110 °C for 15 h in 1,2-dichloroethane under nitrogen atmosphere (entry 1). Subsequent screening of AgSbF6 as an additive led to an enhancement in yield to 72%, whereas AgBF4 and KPF6 produced 25 and 43% yields, respectively (entries 2− 4). In a set of oxidants screened, Ag2CO3, Cu(OAc)2, K2S2O8, AgOAc, and Ag2O, the former produced the best results (entries 5−8). 1,2-Dichloroethane was found to be the solvent of choice, whereas 1,4-dioxane, THF, MeOH, and DMF produced inferior results (entries 9−12). The reactions using RuCl3 and RuCl2(PPh3)3 were not effective, affording 3i in
