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

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Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor St., Chicago, IL 60607, U.S.A
  1. Corresponding author email
Guest Editor: S. R. Chemler
Beilstein J. Org. Chem. 2015, 11, 2097–2104.
Received 11 Aug 2015, Accepted 20 Oct 2015, Published 04 Nov 2015
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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.


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 [1-5]. 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 [6-13]. 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).


Scheme 1: Use of a Chan–Lam reaction for the synthesis of tetrahydroquinolines and potential extension to pyridines [8].

Pyridines are important heterocycles that are often found in biologically active molecules [14-21]. Due to the high demand for these compounds, there are many methods for preparing substituted pyridines through condensation reactions [22-26], cycloadditions [27-30], functionalization of parent pyridine structures [31-38], fragment couplings [39-42], and transition metal-catalyzed C–H bond functionalization of α,β-unsaturated imines and oximes [43-50]. We were inspired by the copper-catalyzed coupling of protected α,β-unsaturated oximes and alkenylboronic acids developed by Liebeskind and coworkers due to its modularity and control of regioselectivity and wondered if a Chan–Lam route to N-alkenylnitrones would allow us to prepare similar intermediates (Scheme 2A) [51]. Nakamura and coworkers have reported that N-allenylnitrones can be accessed through rearrangements of O-propargylic oximes and undergo similar electrocyclizations to form pyridines (Scheme 2B) [52]. Herein, we show that N-alkenylnitrones 8 can be prepared through a Chan–Lam coupling of α,β-unsaturated oximes 6 and an alkenylboronic acids 7 and that these compounds undergo a novel thermal rearrangement to the corresponding tri- and tetrasubstituted pyridines 9 (Scheme 2C). This use of α,β-unsaturated oxime reagents for the synthesis of pyridines is unique from transition metal-catalyzed C–H bond functionalization processes that require a regioselective migratory insertion. This route is appealing due to the modularity of the Chan–Lam coupling process, and proceeds through a pathway that is distinct from the Liebeskind copper-catalyzed C–N bond coupling and electrocyclization (Scheme 2).


Scheme 2: Examples of pyridine synthesis from oxime precursors [51,52].

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.

Table 1: Optimization of Chan–Lam coupling for the synthesis of N-cyclohexenyl-α,β-unsaturated nitrones.a

[Graphic 1]
entry catalyst cat. conc additive yield (%)b
1 Cu(OAc)2 2 equiv none 40
2 Cu(OAc)2 1 equiv none 46
3 CuTC 1 equiv none 30
4 CuBr 1 equiv none dec
5 CuI 1 equiv none trace
6 CuOTf2 1 equiv none trace
7 Cu(TFA)2 1 equiv none trace
8 Cu(OAc)2 10 mol % none 45
9 Cu(OAc)2 30 mol % none 45
10 Cu(OAc)2 10 mol % COE 65
11 Cu(OAc)2 10 mol % NBD 58
12 Cu(OAc)2 10 mol % COD 72
13 Cu(OAc)2 10 mol % 1-octene 57
14 Cu(OAc)2 10 mol % dba 51

aConditions: 6a (1 equiv), 7a (2 equiv), pyridine (5 equiv), Na2SO4 (8–9 equiv), 0.1 M in DCE, 25 °C, air, 18 h. bDetermined by 1H NMR spectroscopy using CH2Br2 as a reference.

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.

Table 2: Scope of N-alkenyl-α,β-unsaturated nitrone synthesis.a

[Graphic 2]
entry 8 yield (%)b entry 8 yield (%)b
1 [Graphic 3]
72c 6 [Graphic 4]
2 [Graphic 5]
41c 7 [Graphic 6]
3 [Graphic 7]
63c 8 [Graphic 8]
4 [Graphic 9]
70e 9 [Graphic 10]
5 [Graphic 11]
84c 10 [Graphic 12]

aConditions: 6 (1 equiv), 7 (2 equiv), pyridine (5 equiv), COD (1.2 equiv), Na2SO4 (8–9 equiv), 0.1 M in DCE, 25 °C, air, 18 h. bPercent isolated yield. cCu(OAc)2 (10 mol %). dCu(OAc)2 (1–2 equiv), pyridine (10 equiv), no COD. eCu(OAc)2 (10 mol %), no COD.

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.


Scheme 3: Solvent effect on conversion of N-alkenylnitrones to pyridines.

Table 3: Scope of conversion of N-alkenyl-α,β-unsaturated nitrones to pyridines.a

[Graphic 13]
entry 9 yield (%)b entry 9 yield (%)b
1 [Graphic 14]
71 6 [Graphic 15]
2 [Graphic 16]
68 7 [Graphic 17]
3 [Graphic 18]
64 8 [Graphic 19]
4 [Graphic 20]
76 9 [Graphic 21]
5 [Graphic 22]
43 10 [Graphic 23]

aConditions: 8 (1 equiv), 4 Å MS, 0.1 M in DMSO, 140 °C, 6–8 h. bPercent isolated yield.

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 1H and 13C NMR spectroscopy. Surprisingly, after heating 8ae for 4 h at 140 °C in DMSO-d6, 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.


Scheme 4: Mechanistic experiments.


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 chalcone- and 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,β-unsaturated 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.
Format: PDF Size: 6.6 MB Download


We acknowledge generous funding from ACS-PRF (DNI-50491), NSF (NSF-CHE 1212895 and 1464115), and the University of Illinois at Chicago. We also thank Mr. Furong Sun (UIUC) for mass spectrometry data.


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