Letter pubs.acs.org/OrgLett
Platinum-Catalyzed Double Acylation of 2‑(Aryloxy)pyridines via Direct C−H Activation Donald C. McAteer, Erman Javed, Lily Huo,† and Shouquan Huo* Department of Chemistry, East Carolina University, Greenville, North Carolina 27858, United States S Supporting Information *
ABSTRACT: A unique, platinum-catalyzed, direct C−H acylation of 2-(aryloxy)pyridines with acyl chlorides is discovered. The reaction requires neither an oxidant nor other additives. When both ortho positions of the aryl group are accessible, the double acylation occurs readily to produce the diacylated products. Aliphatic, aromatic, and α,β-unsaturated acyl groups can all be introduced. The acylation reaction may proceed through an analogous aromatic electrophilic substitution triggered by the nucleophilic attack of the platinum at the acyl chloride.
T
might undergo Pt-catalyzed ortho acylation. Initial attempts to react 2-phenoxypyridine (1a) with benzoyl chloride (2a) (cat. 10 mol % K2PtCl4) in either acetic acid or acetonitrile under reflux did not produce any acylated product. However, when the reaction was carried out at higher temperature in benzonitrile (cat. 10 mol % K2PtCl4) or 1,2-dichlorobenzene [cat. 10 mol % (PhCN)2PtCl2], both mono- and diacylated products were formed. Specifically, the reaction of 1a with benzoyl chloride (5 equiv) in 1,2-dichlorobenzene at 140 °C for 24 h gave predominately the monoacylated product 3aa in 54% isolated yield, along with the diacylated product 4aa in 7% yield (Scheme 1). We then found that when xylene was used as
ransition metal-catalyzed, ligand-directed ortho C−H functionalization of arenes has attracted a great deal of attention over the last two decades.1,2 A wide variety of groups including alkyl, alkenyl, alkynyl, aryl, halogen, acyl, and acetyloxy groups can be introduced, and many different transition metals have been employed in this catalytic process. However, there has been no report on the use of platinum in those ligand-directed ortho C−H functionalization reactions that can be catalyzed by palladium, ruthenium, rhodium, iridium, and copper, among others.2−4 Reported herein is a novel, platinum-catalyzed, direct C−H acylation reaction of 2(aryloxy)pyridines. The carbonyl group is an important functional group that not only is ubiquitous in many pharmaceuticals, natural products, and functional materials but also can undergo a number of transformations into other functional groups. The transitionmetal-catalyzed, directed C−H acylation offers an attractive way to introduce a carbonyl group to aromatic rings selectively,5 which complements or sometimes is advantageous over traditional Friedel−Crafts reaction and other approaches. There are several important reports on palladium-catalyzed ortho-acylation of aromatic compounds with various acylating reagents, including α-oxocarboxylic acids,6 aldehydes,7 alcohols, 8 benzyl ethers,9 benzylamines,10 benzyl halides,11 styrene,12 and toluene derivatives;13 however, all of those reactions require the use of an oxidant to oxidize the acylating reagents and/or regenerate the active catalyst. Several other reports involve the use of acyl chlorides, carboxylic acid anhydride, or carboxylic acids as the acylating reagents in ruthenium-,14 rhodium-,15 and palladium16-catalyzed C−H acylation reactions, respectively, which do not need an oxidant but require an additive such as a base14,15 (up to 5 equiv) or trifluoroacetic anhydride16 (20 equiv). Encouraged by our recent discovery of regiospecific acylation of tridentate C,N,N-coordinated cycloplatinated compounds,17 which produces stable acylated cycloplatinated complexes, we hypothesized that a labile bidentate C,N-coordinating ligand © XXXX American Chemical Society
Scheme 1. Pt-Catalyzed Ortho-Acylation of 2Phenoxypyridine
the solvent the reaction under reflux for 48 h gave diacylated product 4aa in 66% isolated yield, with only a trace amount of monoacylated product 3aa. PtCl2 and (DMSO)2PtCl2 were also effective but less efficient than (PhCN)2PtCl2, resulting in slower reaction. (PPh3)2PtCl2 was not effective under the same reaction conditions. PdCl2, Pd(OAc)2, and (MeCN)2PdCl2 were also tested in this reaction; however, none of them was effective. Further solvent optimization indicated that the use of chlorobenzene resulted in slightly faster reaction and a higher yield of diacylated products, and Scheme 2 lists the structures Received: February 11, 2017
A
DOI: 10.1021/acs.orglett.7b00423 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Pt-Catalyzed Ortho Double Acylation of 2(Aryloxy)pyridinesa
formation. The more sterically hindered aliphatic acyl chloride, trimethylacetyl chloride, did not react to produce the acylated product under the same reaction conditions. α,β-Unsaturated acyl chlorides are significantly more reactive than benzoyl chloride, and the reactions with these substrates was complete within 3−6 h. The moderate yield of 4bf was attributed to the decomposition of the product, as tar materials were formed in the reaction of 3,3-dimethylacryloyl chloride (2f). An electron-withdrawing group in the para position of 2phenoxypyridine deactivated the acylation reaction. For instance, the reaction of 2-(4-chlorophenoxy)pyridine (1d) with benzoyl chloride in chlorobenzene at reflux for 24 h did not produce any appreciable amount of acylated product. However, the reaction with cinnamoyl chloride (2g) proceeded smoothly, and the desired product 4dg was isolated in 64% yield, indicating remarkably high reactivity of the α,βunsaturated acyl chloride. Aroyl chlorides derived from electron-rich arenes such as 4-methoxybenzoyl chloride (2k) and 2-thienylcarbonyl chloride (2l) are less reactive. 2-Furoyl chloride did not react under the same conditions. When one of the ortho positions of 2-phenoxypyridine (1a) was substituted, under the same reaction conditions as described in Scheme 2, the acylation occurred at the other ortho position (3ea, 3ej, and 3ek, Scheme 3). Again, 3Scheme 3. Compounds Synthesized by the Pt-Catalyzed Monoacylation Reaction
a
Conditions: 2-(aryloxy)pyridine (1.0 mmol), acyl chloride (5.0 mmol), Pt(PhCN)2Cl2 (0.1 mmol), chlorobenzene (3 mL), reflux. The reaction time was not optimized. Yields are isolated yields. b Octanoyl chloride (2.5 mmol) was used.
nitrobenzoyl chloride was found to be more reactive than the 4methoxybenzoyl chloride. When the meta position of the 2phenoxypyridine was occupied, only monoacylation occurred at the less sterically hindered ortho position (3fa, 3ga, and 3hj). The acylation of 2-(2-naphthalenoxy)pyridine (1i) occurred at the 3-position of the naphthalene (3ia); apparently, the 1position is more sterically hindered. The electron-withdrawing ethoxycarbonyl group retarded the reaction. Even with more reactive 3-nitrobenzoyl chloride as the acylating reagent, only a low yield of acylated product (3hj) was obtained after 22 h of refluxing in chlorobenzene (Scheme 3). It should be mentioned that when 2-phenylpyridine was used as the substrate there was no ortho acylation under the same conditions. The facile formation of diacylated products is intriguing, since electron-withdrawing groups substantially deactivate the acylation reaction, and the first introduced acyl group should have deactivated the second acylation reaction. To verify if the double acylation can proceed via the acylation of the monoacylated product, the Pt-catalyzed acylation of 3aa was investigated. It turned out that the benzoylation of 3aa with 5 equiv of benzoyl chloride proceeded, albeit at a slow rate, to
of various diacylated 2-(aryloxy)pyridines synthesized by this platinum-catalyzed double acylation reaction. The facile formation of diacylated products was noteworthy. In previously reported ruthenium-catalyzed C−H acylation reaction of 2phenylpyridine and 1-arylpyrazoles, diacylated products were reported as the minor product (
