Copper-mediated synthesis of N-alkenyl-α,β-unsaturated nitrones and their conversion to tri- and tetrasubstituted pyridines

A Chan–Lam reaction has been used to prepare N-alkenyl-α,β-unsaturated nitrones, which undergo a subsequent thermal rearrangement to the corresponding tri- and tetrasubstituted pyridines. The optimization and scope of these transformations is discussed. Initial mechanistic experiments suggest a reaction pathway involving oxygen transfer followed by cyclization.


Introduction
While most applications of the Chan-Lam reaction are focused on the synthesis of aryl ethers and aryl amines, our group has been interested in the use of the Chan-Lam reaction for the synthesis of O-alkenyl oximes and hydroxylamines, as well as N-alkenyl and N-arylnitrones [1][2][3][4][5]. We have discovered that when this transformation is performed with oxime and hydroxamic acid substrates, these reactive intermediates can be accessed and subsequently rearrange to a variety of challenging organic fragments and heterocyclic products [6][7][8][9][10][11][12][13]. Specifically, we reported that N-arylnitrones 3 can be prepared by a Chan-Lam coupling of 1 and 2 and that these compounds undergo a copper-catalyzed rearrangement to α,β-epoxyimines such as 4 [8]. Reduction of these products in the presence of a Lewis acid gave tetrahydroquinolines such as 5 (Scheme 1A). These studies encouraged us to consider if similar N-alkenylnitrones 8 could be accessed by a Chan-Lam coupling and transformed into the corresponding substituted pyridines 9 (Scheme 1B).
Pyridines are important heterocycles that are often found in biologically active molecules [14][15][16][17][18][19][20][21]. Due to the high demand for these compounds, there are many methods for preparing substi-Scheme 1: Use of a Chan-Lam reaction for the synthesis of tetrahydroquinolines and potential extension to pyridines [8].

Results and Discussion
A Chan-Lam coupling between chalcone oxime 6a and cyclohexenylboronic acid (7a) was initially tested using reaction conditions that we had previously identified as optimal for analogous N-alkenylnitrone syntheses from fluorenone oxime [7]. Nitrone 8aa was successfully isolated in 40% yield using 2 equiv of Cu(OAc) 2 and the reaction conditions indicated in Table 1, entry 1. Only the E-nitrone isomer was observed and isolated. Decreasing the amount of copper reagent to 1 equiv had little influence on the reaction and a screen of other common copper salts only resulted in diminished yields ( Table 1, entries 2-7). Further reduction of the copper loading to 10-30 mol % of Cu(OAc) 2 was tolerated without a decrease in reaction efficiency ( Table 1, entries 8 and 9). The key factor in improving the yield of the transformation was identified as an alkene additive. Alkene and alkyne additives have previously been observed to improve similar copper-catalyzed coupling reactions [53]. As shown in Table 1, entries 10-14, the addition of 1.2 equiv of cyclooctadiene (COD), cyclooctene (COE), norbornadiene (NBD), 1-octene, and dibenzylideneacetone (dba) all improved the yield of the Chan-Lam reaction, but COD was most efficient.
Having identified optimal conditions for the synthesis of N-cyclohexenylnitrone 8aa, the scope of the nitrone synthesis was explored by varying the oxime and alkenylboronic acid reagents. As shown in Table 2, chalcone oximes with both electron-rich and electron-poor aryl substituents, as well as heteroaryl substituents, were tolerated for the transformation with electron-donating substituents providing higher yields ( Table 2, entries 1-4). A significant increase in reaction efficiency was also observed for dba oxime ( Table 2, entry 5). Evaluation of acyclic alkenylboronic acids further highlighted the differences between dba oxime and chalcone oximes as substrates for the Chan-Lam reaction. When dba oxime was treated with but-2-en-2-ylboronic acid, nitrone 8eb was isolated in good yield; in contrast, treatment of chalcone oxime with but-2-en-2-ylboronic acid, resulted in the isolation of nitrone 8ab in only 15% yield ( Table 2, entries 6 and 7). Phenyl-substituted alkenylboronic acid 7c and monosubstituted alkenylboronic acids 7d and 7e, were more efficient reaction partners with chalcone oxime and gave the corresponding nitrones in good to excellent yield ( Table 2, entries 8-10). Acyclic alkenylboronic acids were also incompatible with the optimal conditions determined for cyclohexenylboronic acid (7a) and required the use of 1-2 equiv of Cu(OAc) 2 . The use of both copper-catalyzed and copper-mediated reaction conditions with oximes 6 and alkenylboronic acids 7, allowed for the preparation of a variety of N-alkenyl-α,β-unsaturated nitrones to test for further reactivity.
The preparation of the N-alkenyl-α,β-unsaturated nitrones shown in Table 2, allowed for further study of their conversion to tri-and tetrasubstituted pyridines. The preliminary evaluation of this thermal transformation with 8aa indicated that DMSO was a more efficient reaction medium than PhMe, dioxane, or DMF (Scheme 3). As shown in Table 3, all of the chalcone nitrones were readily converted to the corresponding pyridines in good yield (Table 3, entries 1 -4, 6, 8-10). In contrast, the dba nitrones gave the corresponding pyridines in attenuated yields (Table 3, entries 5 and 7). The high density of substituents and regiospecificity of the transformation due to the use of the Chan-Lam reaction for the synthesis of the nitrone  precursor are noteworthy and provide advantages over pyridine syntheses that require regioselective insertion reactions or nucleophilic additions.
To better understand the conversion of N-alkenyl-α,β-unsaturated nitrones 8 to pyridines 9, two mechanistic experiments were evaluated (Scheme 4). The conversion of nitrone 8ae to  pyridine 9ae was monitored by 1 H and 13 C NMR spectroscopy. Surprisingly, after heating 8ae for 4 h at 140 °C in DMSO-d 6 , a 1:1:1 mixture of isoxazoline 15ae, enaminoketone 16ae, and pyridine 9ae was observed [54,55]. Further heating this mixture of intermediates for 4 h resulted in the sole formation of pyridine 9ae. This experiment suggests that the conversion of nitrone 8ae to pyridine 9ae proceeds by oxygen transfer to give 16ae and nucleophilic addition of the enamine to the ketone. This pathway may explain the solvent dependence that was observed for the transformation (Scheme 3). The lack of any observation of dihydropyridine N-oxide intermediate 17ae suggests that the reaction is not proceeding through an electrocyclization and elimination process. A second experiment tested the electronic effect of this oxygen-transfer process. Unsymmetrically substituted dba nitrone 8fa was subjected to the cyclization conditions and a 1:1 mixture of 9fa:9fa' was observed. This experiment indicated a lack of any significant electronic preference for the oxygen-transfer process.

Conclusion
A new method for the preparation of tri-and tetrasubstituted pyridines has been developed that hinges on the use of a Chan-Lam coupling to construct N-alkenyl-α,β-unsaturated nitrone precursors from the corresponding oximes and alkenylboronic acids. This method is tolerant of a variety of chalconeand dba-derived oxime substrates as well as both mono-and disubstituted alkenylboronic acids. Initial reaction monitoring experiments suggest that the cyclization of the N-alkenyl-α,βunsaturated nitrone to the pyridine occurs through an oxygen transfer from the nitrone functionality to the β-position of the conjugated olefin followed by nucleophilic attack of the enamine.

Supporting Information
Supporting Information File 1 Experimental part.