Diversity-oriented functionalization of 2-pyridones and uracils

Heterocycles 2-pyridone and uracil are privileged pharmacophores. Diversity-oriented synthesis of their derivatives is in urgent need in medicinal chemistry. Herein, we report a palladium/norbornene cooperative catalysis enabled dual-functionalization of iodinated 2-pyridones and uracils. The success of this research depends on the use of two unique norbornene derivatives as the mediator. Readily available alkyl halides/tosylates and aryl bromides are utilized as ortho-alkylating and -arylating reagents, respectively. Widely accessible ipso-terminating reagents, including H/DCO2Na, boronic acid/ester, terminal alkene and alkyne are compatible with this protocol. Thus, a large number of valuable 2-pyridone derivatives, including deuterium/CD3-labeled 2-pyridones, bicyclic 2-pyridones, 2-pyridone-fenofibrate conjugate, axially chiral 2-pyridone (97% ee), as well as uracil and thymine derivatives, can be quickly prepared in a predictable manner (79 examples reported), which will be very useful in new drug discovery.

Substrate scope. With the optimal reaction conditions confirmed, we first examined the scope of 2-pyridone, with bromide 2a and styrene 3a as the reaction partners. As shown in Table 2A, a series of 4-iodo-2-pyridones with substitution at C3 or C5 position, including methyl, fluoro, chloro, methyl ether, and ester group, reacted smoothly to provide the alkylated products (4a−4j) in 60-95% yields. The N-substitution of 2-pyridones could be benzyl (4a), methyl (4b), 2,4,6-trimethylbenzyl (Mesityl, 4c), methoxymethyl (MOM, 4d), and p-methoxybenzyl (PMB, 4g). Surprisingly, even the one with free N-H delivered the corresponding product 4e in 69% yield with simultaneous nucleophilic N-alkylation. For ortho-unsubstituted 4-iodo-2-pyridone, the dialkylated product 4l was obtained in 39% yield. Notably, after minor modification of the standard conditions, biologically relevant 6iodo uracil also became a suitable substrate to afford the desired product (4m) in moderate yield. The practicality and robustness of this protocol are evident from the 3.0 mmol scale experiment, which led to a gram-scale preparation of product 4a (1.22 g, 98% yield), alongside the recovery of mediator N 8 in 87% yield.

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Two-component annulation, N-deprotection, and follow-up transformations of the obtained 2-pyridones. Next, we focused on illustrating the synthetic utility of these protocols. First, an annulation process was explored based on a speculated twocomponent Catellani process (Fig. 3A). It was found that 1a reacted with the bifunctional reagent 5 and 6 bearing a bromide and an olefin moiety, to afford the cyclized products 7 and 8 in excellent yields. Thus, it provided an efficient method for the assembly of bicyclic 2-pyridone derivatives [68][69][70] . Then, Ndeprotection of the obtained various 2-pyridones were performed to set the stage for further manipulations (Fig. 3B, C). For example, N-Bn deprotection of 4l′ proceeded smoothly under the catalytic hydrogenation conditions to deliver 9 in 77% yield 71 . The N-PMB group of 4g was readily removed in heated CF 3 CO 2 H to afford 10 72 , which could be quickly transformed into a OTf-substituted pyridine derivative (11) after treatment with Tf 2 O and pyridine 73 . In addition, BBr 3 mediated N-MOM deprotection of 4d took place at a low Table 3 Reaction scope with respect to the terminating reagent. a All reactions were performed on a 0.1-mmol scale. Reported yields are for the isolated products. b Trimethyl(vinyl)silane was used as the olefin. temperature 74 , and the obtained intermediate 12 readily led to pyridine-fused lactone 13 through a facile two-step procedure 75 . Interestingly, BBr 3 mediated N-MOM deprotection of the ortho C-H arylation product 14 provided two products: the normal one 15 in 27% yield and the methyl benzoate hydrolyzed product 16 in 42% yield, which were further transformed into complex pyridine derivatives 17 and 18 respectively in just one step with good yields.
In summary, we have developed a palladium/norbornene cooperative catalysis enabled diversity-oriented functionalization of heterocycles 2-pyridone and uracil. The success of this research depends on the use of two unique norbornene derivatives as the mediator. Readily available alkyl halides/ tosylate and aryl bromides are utilized as ortho-alkylating and -arylating reagents, respectively. Widely accessible ipso-terminating reagents, including H/DCO 2 Na, boronic acid/ester, terminal alkene and alkyne are compatible with this protocol. Thus, a large number of useful derivatives of these heterocycles, including deuterium/CD 3 -labeled 2-pyridones, bicyclic 2-pyridones, 2-pyridone-fenofibrate conjugate, axially chiral 2pyridone (97% ee), as well as uracil and thymine derivatives, can be quickly prepared in a predictable manner, which will be very attractive for developing new generation of EZH2 inhibitors and antiviral agents. This work constitutes not only a nice extention of the Catellani reaction, but also a valuable addition to the toolbox of medicinal chemists

Methods
General procedure for Ortho-alkylating of 2-pyridone. To an oven-dried Schlenk tube equipped with a magnetic stir bar were added Pd(OAc) 2 (5 mol%), norbornene derivatives N 8 (0.05 mmol, 50 mol%), alkenyl iodide 1 (0.12 mmol, 1.2 equiv) and potassium carbonate (0.25 mmol, 2.5 equiv), and anhydrous 1,4-dioxane (1 mL) in the glove box. Then alkylating reagent 2 (0.15 mmol, 1.5 equiv) and terminating reagent 3 (0.1 mmol, 1.0 equiv) were added, and the mixture was heated to 105°C. After completion of the reaction (monitored by TLC (thin layer chromatography), the mixture was cooled to r.t., filtered through a thin pad of celite, eluting with EtOAc   (10 mL), and the combined filtrate was concentrated in vacuo. The residue was directly purified by column chromatography on silica gel or purified by PTLC (preparative thin layer chromatography) to give the desired product.
General procedure for Ortho-arylation of 2-pyridone. To an oven-dried Schlenk tube equipped with a magnetic stir bar were added Pd(OAc) 2 (1 mol%), norbornene derivatives N 9 (0.05 mmol, 50 mol%), alkenyl iodide 1 (0.1 mmol, 1.0 equiv) and potassium carbonate (0.25 mmol, 2.5 equiv), and anhydrous DME (1 mL) in the glove box. Then alkylating reagent 2 (0.15 mmol, 1.5 equiv) and terminating reagent 3 (0.15 mmol, 1.5 equiv) were added, and the mixture was heated to 105°C. After completion of the reaction (monitored by TLC (thin layer chromatography), the mixture was cooled to r.t., filtered through a thin pad of celite, eluting with EtOAc (10 mL), and the combined filtrate was concentrated in vacuo. The residue was directly purified by column chromatography on silica gel or purified by PTLC (preparative thin layer chromatography) to give the desired product.