Chinese Chemical Letters  2014, Vol.25 Issue (12):1515-1519   PDF    
A novel and facile synthesis of 2-oxo-1,2-dihydropyridine-fused 1,3-diazaheterocycles via heterocyclic keteneaminalsandKonevenagel adducts formed by phthalic anhydride and ethyl cyanacetate
Min-Ming Zou, Feng-Juan Zhu, Xue Tian, Li-Ping Ren, Xu-Sheng Shao , Zhong Li    
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
Abstract: An efficient synthetic pathway to 2-oxo-1,2-dihydropyridine-fused 1,3-diaza heterocycles from heterocyclic ketene aminals, phathalic anhydride and ethyl cyanacetate was established. This protocol involved aza-ene reaction/imine-enamine tautomerization/enamine-ester exchange/ring-opening reaction sequence.
Key words: Heterocyclic ketene aminals     2-Oxo-1,2-dihydropyridine     1,3-Diazaheterocycle     Synthesis    
1. Introduction

Modern organic chemistry is more and more related to heterocycles. Developing novel heterocycles and relating synthetic methods is the eternal goal in synthetic chemistry [1]. Of particular interest is the nitrogen-containing heterocycles due to their existence in many natural or synthetic molecules [2]. Despite diverse synthetic utility,exploring novel synthetic methods to meet increasing scientific and practical demands is still an active area.

Heterocyclic ketene aminals (HKAs) are important versatile intermediates in synthetic chemistry [3]. Moreover,HKAs per se and their derivatives exhibited pharmaceutical [4] or pesticidal activity [5]. Their usage for constructing a variety of nitrogencontaining heterocycles or fused heterocyclic compounds has been extensively studied [6]. The notable feature of HKAs is the highly polarized ethylene systems with electro-donating amino group and electro-withdrawing substituent at two ends (Fig. 1). This unique structural feature makes them serve as bis-nucleophiles reacting with various bis-electrophiles [3].

Fig. 1.Heterocyclic ketene aminals.
2. Experimental

Our interests in HKAs chemistry involved the preparation of bioactive molecules using them and their methodology studies [5, 7]. During previous investigation,we found that HKA 1 could react with cyclic Knoevenagel adducts (KAs) 2,3 and 4 affording the corresponding spiro-heterocyclic compounds 6,7 and 8. However, when the same type of KA 5 was employed,an unknown product instead of spiro-heterocyclic product 9 formed. Further structural analysis proved that this new product was 10 (Fig. 2). The above unexpected results were especially interesting and useful because they provided an novel way for entry to 2-oxo-1,2- dihydropyridine-fused heterocycles. As there were only two reports on the access of this kind of novel heterocycles via azaene reaction,cyclization and oxidation [6h, 6g],it was necessary to develop this novel methodology.

Fig. 2.Reaction of HKAs with cyclic Knoevenagel adducts.

In the current study,we wish to report a facile synthesis of 2- oxo-1,2-dihydropyridine-fused 1,3-diazaheterocycles from HKAs, phthalic anhydride and ethyl cyanacetate. Moreover,this method provided the possibility for assembling benzoic acid subunit which can be utilized for further derivatization since the introduction of this substituted pattern is still remaining difficult.

For the purity of KA 5 is of critical importance,initially,its preparation was investigated. The conversion of phthalic anhydride to KA 5 was attempted by a two-step process consisting of the addition of ethyl cyanacetate under diisopropylamine (DIPA) and THF followed by cyclization in SOCl2 and dichloromethane (DCM). In a preliminary experiment,TLC analysis of the reaction mixture indicated that only one product existed in the reaction mixture. After purification,however,ultra performance liquid chromatography (UPLC) and 1H NMR showed that the product was a mixture of 5 and phthalic anhydride (with a ratio of 1:5) which had similar Rf values. Further study elucidated that treatment of phthalic anhydride with DIPA would also lead to the formation of salt 12 which could convert to phthalic anhydride during cyclization. By careful selection of eluting solvents,the pure KA 5 was successfully obtained eluting by DCM/n-hexane (2:1,v:v) (Fig. 3).

Fig. 3.Synthesis of KA 5.

With the pure 5 in hand,we next optimized the reaction conditions for this transformation. As a model reaction, 2-(nitromethylene) octahydro-1H-benzo[d]imidazole 13 and 5 were treated with different solvents at varied temperature (Table 1). A rapid screen of solvents at 50 ℃ without catalysts showed significant reduction of the formation of 14 when the reaction was carried out in nonpolar or low polar solvents (such as THF and toluene). DMF was used for further evaluation due to the high conversion. Elevating temperature to 70 ℃ resulted in the highest yields (93%). When the reaction temperature went above 70 ℃,slight decomposition of 5 was observed. Acid or base did not show any increases in production rate on this transformation.

Table 1
Optimization of reaction of HKA 13 with 5.
3. Results and discussion

Under the optimal conditions (DMF,70 ℃),a variety of HKAs were examined to probe the generality as well as the limitation of this novel method. The results were summarized in Table 2. This protocol was tolerant to various HKAs. The electron-withdrawing ability ofEWGhad a great influence on the reaction proceeding. For substrates with strong electron-withdrawing group (-NO2 or -CN), the products were obtained in excellent yields (entries 1-10, around 90%). In cases where the EWG was -COOR or -COR,the reactions afforded products in lower yields due to the poorer electron-withdrawing ability (entries 11-15). The cycle patterns and the electronic properties of substituents on nitrogen in HKAs had little effect on this transformation.

Table 2
Synthesis of 2-oxo-1,2-dihydropyridine-fused 1,3-diazaheterocycles.

The structures of the products were well characterized by NMR and HRMS studies. Furthermore,diffraction studies allowed for the unambiguous confirmation of the inferred structure (Fig. 4).

Fig. 4.ORTEP drawing of 2-(6-cyano-8-nitro-5-oxo-1,2,3,5-tetrahydroimidazo[1,2- a]pyridin-7-yl)benzoic acid.

Although the mechanism of reaction was not established experimentally,a possible explanation was proposed here to elucidate this conversion. The transformation proceeded in the following sequential reactions (using HKA 13 as example),aza-ene reaction,imine-enamine tautomerization,enamine-ester exchange and ring-opening reaction (Fig. 5).

Fig. 5.Proposed mechanism for the formation of 2-oxo-1,2-dihydropyridine-fused 1,3-diazaheterocycle.
4. Conclusion

In conclusion,we developed a procedure for the convenient synthesis of 2-oxo-1,2-dihydropyridine-fused 1,3-diazaheterocycles by simply stirring a mixture of knoevenagel adduct formed by phthalic anhydride and ethyl cyanacetate and heterocyclic ketene aminal. This transformation presented a novel method for the construction of 2-oxo-1,2-dihydropyridine-fused 1,3-diazaheterocycles. Moreover,the benzonic acid subunit was simultaneously introduced,which made them easy for further transformation for constructing derivatives with biological importance.


This work was financial supported by National Natural Science Foundation of China (No. 21372079),National High Technology Research Development Program of China (863 Program,No. 2011AA10A207),Shanghai Pujiang Program (No. 14PJD012),Key Projects in the National Science & Technology Pillar Program (No. 2011BAE06B05),and the Fundamental Research Funds for the Central Universities. This work was also partly supported by Australia DC Foundation.

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