DBU‐Promoted 6π‐Azaelectrocyclization and Hydrogen‐Migration to Prepare 6‐Alkyl Pyridine N ‐Oxides from N ‐Vinyl‐ α , β ‐Unsaturated Nitrones

We describe a DBU‐controlled 6π‐azaelectrocyclization of dibenzylideneacetone‐derived N‐vinyl‐α,β‐unsaturated nitrones to prepare 6‐alkyl pyridine N‐oxides in 24–82% yields. Mechanistic studies revealed that DBU had a great impact on the formation of 6‐alkyl pyridine N‐oxides and served as a base and the carrier of hydrogen sources to in situ reduce C=C bonds. The 6‐alkyl pyridine N‐oxide was prepared at gram‐scales and converted to estrone‐derived pyridine and pyrido[2,3‐c]carbazole 4‐oxide in 46% and 52% yields in two steps, respectively.

Keywords: nitrones; 6π-azaelectrocyclization; pyridine N-Oxides; hydrogen-migration; N-heterocycle

Pyridine N‐oxides are one important class of N‐heterocyclic compounds in natural products and serve as useful building blocks in organic synthesis.[1] These compounds are not only elegant ligands or oxidants as O‐sources owing to their donor properties but also important starting materials to access pyridine derivatives.[2] Conventional strategies to prepare pyridine N‐oxides were through direct oxidation of pyridine derivatives with oxidants, such as m‐CPBA, or H2O2, etc.[3] Due to the significant importance of these compounds, elegant methods have been developed to prepare pyridine N‐oxide derivatives, such as selective C−H bond functionalization of pyridine N‐oxides,[4] or other related transformations.[5] However, these methods usually suffered from functional group tolerance owing to the use of strong oxidants, multiple synthesis of starting materials, or the use of pyridine N‐oxides as starting materials. Therefore, the development of new strategies to access pyridine N‐oxide derivatives is in great demand.

6π‐Azaelectrocyclization,[6] one of the well‐known concerted pericyclic reactions, represents an elegant annulation approach for the synthesis of N‐heterocycles and has attracted great interest in the synthesis of pyridines,[7] quinoxalines and quinolines,[8] and azepines.[9] Some of these strategies have been successfully applied in the total synthesis of natural products and biologically active molecules.[10] However, few examples were reported to prepare pyridine N‐oxides through 6π‐azaelectrocyclization. In 2010, Nakamura and co‐workers pioneered to report a copper(I)‐catalyzed 2,3‐rearrangement of (E)‐O‐propargylic α,β‐unsaturated oximes and sequential 6π‐azaelectrocyclization of N‐allenyl nitrone intermediates to synthesize polysubstituted pyridine N‐oxides in good to high yields (Scheme 1‐A).[11] Recently, N‐vinyl‐α,β‐unsaturated nitrones have been gained much attention owing to their easy preparation through copper‐catalyzed Chan‐Lam coupling reaction of α,β‐unsaturated oximes with vinylboronic acids under mild reaction conditions.[12,13] During the studies of the application of N‐vinyl‐α,β‐unsaturated nitrones in our group, we found that N‐vinyl‐α,β‐unsaturated nitrones could undergo various O‐5‐endo‐trig cyclizations to afford polysubstituted pyridine derivatives in the presence of iron(III) or nickel(II) catalysts (Scheme 1‐B).[14] We surmised that N‐vinyl‐α,β‐unsaturated nitrones could initially undergo a 6π‐azaelectrocyclization and aromatization in the presence of a base will produce 6‐vinyl pyridine N‐oxides. To our surprise, we found that N‐vinyl‐α,β‐unsaturated nitrones were converted to 6‐alkyl pyridine N‐oxides rather than 6‐vinyl pyridine N‐oxides in the presence of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU), showing that hydrogen‐migration occurred during the aromatization of 6π‐azaelectrocyclization products. Herein, we reported that N‐vinyl‐α,β‐unsaturated nitrones underwent a 6π‐azaelectrocyclization to afford dihydropyridine N‐oxide intermediates, and subsequent DBU‐controlled hydrogen‐migration to prepare 6‐alkyl pyridine N‐oxides in good yields (Scheme 1‐C).

Initially, N‐vinyl‐α,β‐unsaturated nitrone (1 a) easily prepared from the copper(II)‐mediated cross‐coupling reaction of α,β‐unsaturated oximes and vinylboronic acids[14,15] was selected as a model substrate to test the 6π‐azaelectrocyclization. As shown in Table 1, nitrone 1 a was conducted in toluene without any base at 120 °C for 8 h affording 6‐vinylpyridine N‐oxide 3 a in only 12% yield and 6‐alkyl pyridine N‐oxide 2 a was not observed (Table 1, entry 1). However, when 1 a was carried out in the presence of 2.0 equiv. of DBU as a base, the desired 6‐alkyl pyridine N‐oxide 2 a was obtained in 75% yield (Table 1, entry 2). The structure of compound 2 a was determined by X‐ray diffraction analysis, showing that the C=C double bond in 3 a was reduced to alkyl groups (Figure 1).[16] Interestingly, the influence of bases screening showed that other organic or inorganic bases, such as NEt3, i‐Pr2NEt, DMAP, and DBACO did not afford 6‐alkyl pyridine N‐oxide 2 a and only furnished 3 a in lower yields with some decomposition of 1 a (Table 1, entries 3–6). Interestingly, 1,5‐diazabicyclo[4.3.0]‐5‐nonene (DBN) afforded 2 a in 71% yield and 3 a was not observed (Table 1, entry 7). Inorganic base such as KOH only resulted in 3 a in 10% yield (Table 1, entry 8). The solvent screening by using DBU revealed that most solvents gave 2 a in moderate yields whereas MeOH gave 2 a and 3 a in 21% and 15% yields, respectively (Table 1, entries 9–15). Increasing the amount of DBU to 3.0 equiv. improved the yield of 2 a to 82% while reducing the amount of DBU diminished the yields of 2 a (Table 1, entries 16–19). Lowering the temperature to 100 °C or 80 °C afforded 2 a in 72% and 46% yields, respectively, but the reaction required longer reaction time (Table 1, entries 20 and 21). Therefore, the optimal conditions for the preparation of 6‐alkyl pyridine N‐oxide 2 a was DBU (3.0 equiv.) in toluene at 120 °C for 3 h.

1 TableOptimization of reaction conditions. [a]

entry	base	solvent	2 a, %[b]	3 a, %[b]
1	–	toluene	<5	12
2	DBU	toluene	75	<5
3	NEt3	toluene	<5	27
4	i‐Pr2NEt	toluene	<5	23
5	DMAP	toluene	<5	24
6	DABCO	toluene	<5	36
7	DBN	toluene	71	<5
8	KOH	toluene	<5	10
9	DBU	CHCl3	53	<5
10	DBU	THF	27	<5
11	DBU	MeCN	41	<5
12	DBU	dioxane	55	<5
13	DBU	DMF	58	<5
14	DBU	DMSO	32	<5
15	DBU	MeOH	21	15
16[c]	DBU	toluene	82	<5
17[d]	DBU	toluene	69	<5
18[e]	DBU	toluene	60	<5
19[f]	DBU	toluene	48	<5
20[c],[g]	DBU	toluene	72	<5
21[c],[h]	DBU	toluene	46	<5

1 [a] Reaction conditions: 1 a (0.2 mmol), base (0.4 mmol, 2.0 equiv.), solvent (2.0 mL), 120 °C, 3–8 h; [b] isolated yield; [c] DBU (3.0 equiv.); [d] DBU (1.0 equiv.); [e] DBU (0.5 equiv.); [f] DBU (0.2 equiv.); [g] at 100 °C, 12 h; [h] at 80 °C, 24 h.

With the optimized conditions in hand, the substrate scope of preparing 6‐alkyl pyridine N‐oxides 2 was explored by testing various N‐vinyl‐α,β‐unsaturated nitrones. As shown in Table 2, a variety of dibenzylideneacetone‐derived N‐vinyl nitrones 1 a–1 l bearing electron‐donating and electron‐withdrawing groups at the para‐, meta‐, ortho‐positions of the aryl ring proceeded smoothly to furnish the corresponding products 2 a–2 l in good yields. Nitrones 1 m with 2‐furanyl and 1 n with 2‐thienyl also tolerated to afford products 2 m and 2 n in 59% and 62% yields, respectively. In addition to dibenzylideneacetone moieties, the vinyl moieties on the N‐atom of nitrones were also evaluated. The vinyl moieties of nitrones tolerated linear and cyclic substituents and afforded the corresponding products 2 o–2 w in moderate to good yields. When the R3 was a phenyl, the yields were dropped dramatically (2 q–2 r). The N‐vinyl groups were also compatible with six‐ to eight‐carbon rings and pyran ring on the N‐atom (2 s–2 v). Pleasingly, nitrone 1 w with an acetal group on the six‐membered ring also successfully afforded 2 w in 44% yield. When a 1:1 E/Z mixture of nitrone 1 x with OMe was subjected to the optimized conditions, product 2 x was obtained in 60% yield with a 1.3:1 ratio. However, a 1:1 E/Z mixture of nitrone 1 y with CF3 delivered product 2 y in 50% yield with a 1:1.3 ratio, showing the electron‐donating groups facilitated to undergo 6π‐azaelectrocyclization. The structures of these two isomers of compounds 2 x and 2 y were determined by their 2D NMR and NOESY spectra, respectively.

2 [a] Reaction conditions: 1 (0.2 mmol), DBU (0.6 mmol, 3.0 equiv.), toluene (2.0 mL), 120 °C, 3–8 h; [b] isolated yield; [c] the isomeric ratio of 2 x and 2 y was determined by 1H NMR.

To better understand the mechanism for the formation of 2 a, control experiments were performed (Scheme 2). It was found that 2 a and 3 a cannot be converted into each other under the optimized conditions or under the thermal conditions with NEt3 as base (Scheme 2–1). These reactions suggested that DBU might not be the active species to reduce the double bond of 3 a to afford 2 a. When D‐1 a was subjected to the optimized conditions, D‐2 a was obtained in 78% yield with a 12% D at the Ha and a 20% D at the Hb (Scheme 2–2). When 10.0 equiv. of D2O was added to the optimized conditions, D‐2 aa was obtained in 73% yield with a 30% D at the Ha and Hb (Scheme 2–3). These results indicated that there were H/D exchanges in the reactions. Using a 1:1 E/Z mixture of D‐1 aa afforded 2 a and D‐2 aaa in 76% yield with a 1:1 ratio of 2 a and D‐2 aaa (Scheme 2–4). When a 1:1 mixture of 1 a and D‐1 a was conducted at the optimized conditions, a 1:1 mixture of 2 a and D‐2 aaa was obtained in 70% yield (Scheme 2–5). These results suggested that 6π‐azaelectrocyclization might be not a rate‐determining step. The reaction was also monitored by 1H NMR trace experiments (See more details in Supporting Information). The 6π‐azaelectrocyclization intermediate A was observed and accumulated, which was finally converted to product 2 a as the reaction time. These results suggested that 6π‐azaelectrocyclization might be not a rate‐determining step, which was in agreement with the results of Scheme 2–5.

The effect of the DBU equivalents on the yield of 2 a was studied. Nitrone 1 a was carried out in the presence of 0.5, 1.0, 2.0, and 3.0 equiv. of DBU. As shown in Figure 2, experimental results shown that the reaction efficiency varied from different equivalents of DBU and 3.0 equivalents of DBU were more rapid than using other equivalents giving a better yield of 2 a in the same reaction time. The conversion rate of nitrone 1 a did not have a linear correlation with the yield of forming product 2 a (See more details in Figure S2 in Supporting information). The non‐linearity of yield and conversion observed for DBU indicated that the reaction was not a first‐order reaction for DBU reagent. The DBU reagent participated into the rate‐determining step and had a great impact on the reaction rate.

To investigate the independence of initial rate of 6π‐azaelectrocyclization, the electronic nature of aryl group at the styryl group was studied. Competition experiments between para‐substituted aryl moieties of nitrones 1 b–1 d, 1 f–1 g and 1 a were used to test the formation of 2 a by comparison of the relative to σp and σm values, respectively.[17] As shown in Figure 3, the relative rate dependence on the para‐substituted aryl moieties of nitrones had a linear correltion with σp and the ρ‐value is −0.284, whereas a nonlinear correlation with σm‐value was obtained. The negative ρ‐value might indicate that the electron‐donating groups facilitated to undergo 6π‐azaelectrocyclization and form product 2 a. These results are in accordance with the results of 2 x and 2 y in Table 2.

Based on the above results and HRMS (ESI) trace experiments of intermediates,[18] a possible mechanism for the formation of 2 a and 3 a was proposed (Scheme 3). Initially, nitrone 1 a undergoes a 6π‐azaelectrocyclization to afford cis‐intermediate A under the thermal conditions, which undergoes hydrogen‐transfer to give 6‐vinyl pyridine N‐oxide 3 a and releases DBU−H2 via intermediate B. Both DBU−H2 and intermediate B were detected by HRMS (ESI) experiments. Finally, compound 3 a was reduced in situ by DBU−H2 to afford 6‐alkyl pyridine N‐oxide 2 a and releases DBU. Therefore, using catalytic amount of DBU (0.2 equiv.) also provides 2 a in moderate yield (see Table 1, entry 19). Alternatively, intermediate A could also be directly oxidized by air to give compound 3 a in the presence of other bases. From the whole mechanism we can see that DBU played as a base and the carrier of H‐sources to reduce C=C double bond.

To demonstrate the usefulness of these pyridine N‐oxides, gram‐scale preparation of 2 a was performed. As shown in Scheme 4–1, 1.5 g of nitrone 1 a was carried out in the presence of DBU affording 2 a in 83% yield (1.26 g). Treating 2 a with Ac2O and subsequent deprotection with K2CO3 furnished compound 4 in 66% yield. Then, an estrone‐derived pyridine 5 was obtained in 70% yield through a bromination with PBr3 and substitution with estrone under mild conditions. Deprotection of pyridine N‐oxide 2 w with concentrated HCl afforded compound 6 in 90% yield, which was converted to pyrido[2,3‐c]carbazole 4‐oxide 7 in 58% yield through Fischer indole synthesis (Scheme 4–2). The structure of compound 7 was determined by X‐ray diffraction analysis.[16]

In summary, we have developed a 6π‐azaelectrocyclization of N‐vinyl‐α,β‐unsaturated nitrones and subsequent DBU‐controlled hydrogen‐migration to prepare 6‐alkyl pyridine N‐oxides. The reaction showed broad substrate scope of N‐vinyl‐α,β‐unsaturated nitrones and tolerated various functional groups. Experimental results showed that DBU was served as a base and the carrier of hydrogen sources to in situ reduce C=C double bond. Furthermore, an estrone‐derived pyridine and pyrido[2,3‐c]carbazole 4‐oxide were obtained easily in 46% and 52% yields over two steps, respectively.

Experimental Section

General procedure for the synthesis of 6‐alkyl pyridine N ‐oxides 2: In a 25 mL reaction flask was charged with N‐vinyl nitrone 1 (0.2 mmol), DBU (91.3 mg, 0.6 mmol, 3.0 equiv.) and toluene (2 mL). Then, the reaction vessel was sealed with a Teflon cap. The reaction mixture was stirred vigorously at 120 °C for 3–8 h until nitrone 1 was consumed completely (monitored by TLC). At this time, the solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (1/6 to 5/1, ethyl acetate/petroleum ether) to afford 6‐alkyl pyridine N‐oxides 2.

Acknowledgements

Financial support from the NSFC (21871062, 22071035) and Innovation project of Guangxi Graduate Education (YCBZ2021039), is greatly appreciated.

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GRAPH: Supporting Information

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By Ning Zou; Zhang‐Wei Liu; Gong‐Gui Yan; Ying‐Chun Wang; Cui Liang and Dong‐Liang Mo

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