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Ruthenium(II)-Catalyzed Positional Selective C-H Oxygenation of N-Aryl-2-pyrimidines Tanumay Sarkar, Sourav Pradhan, and Tharmalingam Punniyamurthy J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00714 • Publication Date (Web): 15 May 2018 Downloaded from http://pubs.acs.org on May 15, 2018
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The Journal of Organic Chemistry
Ruthenium(II)-Catalyzed Positional Selective C-H Oxygenation of N-Aryl-2pyrimidines Tanumay Sarkar, Sourav Pradhan and Tharmalingam Punniyamurthy* Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati, 781039, India.
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.
INTRODUCTION The transition-metal-catalyzed directed C–H bond functionalization has emerged as a reliable synthetic toolbox 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 co-workers reported an oxime-directed Pd-catalyzed acetoxylation of C-H bonds using PhI(OAc)2 as an acylating agent,2a while Yu and co-workers demonstrated an oxazoline directed Pd-catalyzed acetoxylation of methyl C-H bond utilizing acid anhydride as an acyl
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The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
source.2b Several studies on oxygenation of C-H bonds have been subsequently reported employing Pd and Cu-based catalytic systems with PhI(OAc)2,4 anhydride,5b,6b tert-butyl peroxyacetate,6c acid halide6d 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 triazole7c and anilide7a based directing groups are studied utilizing Pd, Rh, Ru, Cu and Co-based catalytic systems (Scheme 1b). This strategy is attractive as they are atom economical and can lead to diverse ester scaffolds. Being a recurring moiety in bio-active molecules,8 pyrimidine based σ-coordinating group is
Scheme 1. Methods for Directed Regioselective C-H Oxygenation of Arenes Previous studies DG
DG
O
Pd, Cu a)
Me O
acetyl source acetoxylation: well studied DG DG
DG
O
Rh, Pd, Ru, Cu, Co
b)
Ar O
ArCOOH benzoxylation: limited studies
DG = oxazoline, carboxamide, sulfoximine, pyridyl, triazole,anilide c) This study 2-pym
2-pym
NH Ru RCO 2H
NH O
R
pym = pyrimidyl
O
Advantages: R = aryl, alkyl, heteroaryl functional group diversity gram-scale synthesis
employed as directing group for the C-H functionalization.9 In continuation of our studies on directed C-H functionalization,10 we here report an efficient Ru-catalyzed11,12 ortho-selective
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The Journal of Organic Chemistry
oxygenation of N-aryl-2-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 the important practical features.
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, the reaction occurred to produce the ester 3i in 39% yield when the substrates were stirred employing 5 mol % [RuCl2(p-cymene)]2, 20 mol % AgOTf and 2 equiv 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
