Pd-Catalyzed Three-Component Chemospecific Allylic Substitution Cascade for the Synthesis of N-Carbonylmethylene-2-Pyridones

doi:10.6023/A19060210

Acta Chimica Sinica ›› 2019, Vol. 77 ›› Issue (10): 993-998.DOI: 10.6023/A19060210 Previous Articles Next Articles

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钯催化三组分烯丙基串联反应: 化学专一性合成N-酰亚甲基-2-吡啶酮

姚坤^a, 刘浩^a, 袁乾家^a, 刘燕刚^a, 刘德龙^a^*(), 张万斌^a^b^*()

^a 上海市手性药物分子工程重点实验室上海交通大学药学院上海 200240
^b 上海交通大学化学化工学院上海 200240

投稿日期:2019-06-13 发布日期:2019-08-15
通讯作者: 刘德龙,张万斌 E-mail:dlliu@sjtu.edu.cn;wanbin@sjtu.edu.cn
基金资助:
项目受国家自然科学基金(21971162);项目受国家自然科学基金(21672142);项目受国家自然科学基金(21620102003);项目受国家自然科学基金(21831005);上海市教委(201701070002E00030)

Pd-Catalyzed Three-Component Chemospecific Allylic Substitution Cascade for the Synthesis of N-Carbonylmethylene-2-Pyridones

Yao, Kun^a, Liu, Hao^a, Yuan, Qianjia^a, Liu, Yangang^a, Liu, Delong^a^*(), Zhang, Wanbin^a^b^*()

^a Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiaotong University, Shanghai 200240
^b School of Chemistry and Chemical Engineering, Shanghai Jiaotong University, Shanghai 200240

Received:2019-06-13 Published:2019-08-15
Contact: Liu, Delong,Zhang, Wanbin E-mail:dlliu@sjtu.edu.cn;wanbin@sjtu.edu.cn
Supported by:
Project supported by the National Natural Science Foundation of China(21971162);Project supported by the National Natural Science Foundation of China(21672142);Project supported by the National Natural Science Foundation of China(21620102003);Project supported by the National Natural Science Foundation of China(21831005);Shanghai Municipal Education Commission(201701070002E00030)

1. Pd-Catalyzed Three-Component Chemospecific Allylic Substitution Cascade for the Synthesis of N-Carbonylmethylene-2-Pyridones.pdf(5369KB)

Abstract

Functionalized N-carbonylmethylene-2-pyridones are some of the most important structural motifs and exist in many natural products and bioactive compounds. Thus, the efficient construction of such skeletons has attracted much attention. Generally, the synthesis of N-carbonylmethylene-2-pyridones is realized via an intermolecular nucleophilic substitution of 2-hydroxypyridines and appropriate electrophiles. However, the above reactions often suffer from low yields caused by poor O/N chemoselectivities due to the dual nucleophilicity of the 2-hydroxypyridines. As far as the structure is concerned, N-carbonylmethylene-2-pyridones can be divided into three sections: a pyridone, a carbonylmethyl group and a side chain. When the side chain is a H atom, the N-substituted pyridones can be constructed conveniently via a reaction of 2-hydroxypyridines and primary α-bromocarbonyl compounds in high yields with excellent chemoselectivities. However, when the side chain is not a H atom, for example an alkyl group, only limited examples have been reported and only moderate yields of the desired N-substituted pyridine products are obtained by a combination of 2-hydroxypyridines and bulky secondary α-bromocarbonyl compounds, mainly due to the poor O/N chemoselectivities. To achieve a general synthetic pathway for the latter, the following practical strategy was designed. 2-Hydroxypyridines were first treated with primary α-bromocarbonyl compounds to generate the unique N-substituted intermediates in situ, which then reacted with the side chain electrophiles to give only the N-alkylated final products. Thus, a Pd-catalyzed three-component chemospecific allylic substitution cascade has been developed for the synthesis of N-carbonylmethylene-2-pyridone derivatives, with the desired products being obtained in up to 98% yield. No O-alkylated by-product was observed. The results suggested that the N-carbonylmethylene-2-pyridones are constructed via a cascade reaction consisting of a nucleophilic substitution followed by an allylic alkylation. The reaction was performed on a gram scale and the corresponding alkylated product was conveniently converted to a pyridone-containing unnatural amino acid. This methodology allows for the highly chemoselective synthesis of biologically important N-carbonylmethylene-2-pyridone derivatives.

Key words: allylic substitution cascade, three-component, chemospecificity, N-carbonylmethylene-2-pyridone

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Yao, Kun, Liu, Hao, Yuan, Qianjia, Liu, Yangang, Liu, Delong, Zhang, Wanbin. Pd-Catalyzed Three-Component Chemospecific Allylic Substitution Cascade for the Synthesis of N-Carbonylmethylene-2-Pyridones[J]. Acta Chimica Sinica, 2019, 77(10): 993-998.

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Fig. & Tab. 7

Figure 1. N-Carbonylmethylene-2-pyridones

Scheme 1. Construction of functionalized N-substituted-2-pyridones

Table 1. Exploration of the allylic substrates

Table 2. Exploration of the allylic substrates and α-bromoketones

Scheme 2. Study on step by step reaction

Scheme 3. Proposed reaction pathway

Scheme 4. Gram-scale synthesis of 5a and transformation of 4a

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钯催化三组分烯丙基串联反应: 化学专一性合成N-酰亚甲基-2-吡啶酮

Pd-Catalyzed Three-Component Chemospecific Allylic Substitution Cascade for the Synthesis of N-Carbonylmethylene-2-Pyridones

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Fig. & Tab. 7

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