叔丁基-4-取代-3-羰基-2,8-二氮杂螺[4.5]癸烷-8-羧酸酯类化合物的合成
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摘要
本论文主要研究了以N-Boc-4-哌啶酮为原料合成叔丁基4-取代-3-羰基-2,8-二氮杂螺旋[4.5]癸烷-8-羧酸酯类化合物的三种不同方法。讨论了各个方法的优缺点,确定了其适用范围,合成的16个最终产品都经过1H NMR、13C NMR、 ESI-MS的鉴定,39个中间体都经过1HNMR的鉴定。
路线一：以N-Boc-4-哌啶酮为原料,先通过Wittig反应生成α，β不饱和酯2a-c、再由Michael加成反应引入硝基、最后还原硝基并原位环合得到二氮杂螺环化合物4a-b。此方法的关键步骤是硝基甲烷的Michael加成反应,当R=H时,合成得到4a,总收率60%。但当R=Me时,虽尝试用多种刘易斯酸作为催化剂,但Michael加成反应的产率没有明显提高,仅为18%。当R=Et时,则没有得到对应的Michae1加成反应产物。因此,此路线适用于合成羰基a-H没有被取代的螺环化合物(Scheme1)。
路线二：先由硝基甲烷对N-Boc-4-哌啶酮进行亲核加成和消去反应生成α，β-不饱和硝基化合物12,继而通过Michael加成反应引入α-取代的酯基得到化合物13,最后还原硝基并关环得到目标产品14。此方法适用于芳香环取代羰基a-H的螺环化合物的合成,单步反应收率达到中等及中等以上(Scheme2)。
路线三：先用路线一合成3-羰基-2,8-二氮杂螺[4.5]癸烷4a,再保护酰胺氮得到化合物15,经过螺环羰基α-位的修饰得到化合物16、17、18,最后脱除酰胺氮的保护基得到4-取代-3-羰基-2,8-二氮杂螺[4.5]癸烷类螺环化合物19和20。此路线的关键步骤是羰基α-位的SN2亲核取代反应,一切对亲核取代反应有利的条件都能促进反应进行,提高收率。此路线适用于烷基取代的二氮杂螺环化合物的合成,单步反应收率在中等及中等以上(Scheme3)。
In this thesis,4-substituted tert-butyl3-oxo-2,8-diazaspiro[4.5]decane-8-car-boxylates were synthetized in three different methods using tert-butyl4-oxopiperid-ine-l-carboxylate as starting material. The advantages and disadvantages and application scope of each method were discussed. Sixteen target pruducts have been prepared and characterized by]H NMR、13C NMR、ESI-MS. All of the intermediates identified by'H NMR.
Strategy one:The α,/β-unsaturated esters2a-c were abtained from tert-butyl4-oxopiperidine-l-carboxylate by using Wittig reaction. After undergoing Michael addition, reduction, and cyclization the desired diazaspiro compounds4a-b were obtained. The key step of this method was Michael addition reaction of the nitromethane, when R=H, the yield of4a was60%. When R=Me, the yield of the Michael addition did not increase obviously (only18%) although a variety of Lewis acids were used as catalyst. When R=Et, the corresponding Michael addition reaction product was not found. Therefore, this route could only be used to synthsize the spiro compounds which have no substituted groups (Scheme1).
Strategy two:The α,β-unsaturated nitro compound12was generated from tert-butyl4-oxopiperidine-l-carboxylate1by using nucleophilic addition reaction and elimination reaction. Then a-substituted ester was introduced in by Michael addition reaction. After reduction of nitro and cyclization, the target products were obtained in moderate to good yields. This method could be applied to provide the derisved products which have the aromatic substituted group (Scheme2).
Strategy three:Compound4a was firstly obtained by using strategy one, then protecting the amide nitrogen, modifying the a-site of carbonyl and removing the protecting group,4-substituted tert-butyl3-oxo-2,8-diazaspiro[4.5]decane-8-carbox-ylates19-20were produced. The key step of this route was the SN2reaction. This route was applicable to provide the4-alkyl diazaspiro compouds in moderate to good yields (Scheme3).
路线一：以N-Boc-4-哌啶酮为原料,先通过Wittig反应生成α，β不饱和酯2a-c、再由Michael加成反应引入硝基、最后还原硝基并原位环合得到二氮杂螺环化合物4a-b。此方法的关键步骤是硝基甲烷的Michael加成反应,当R=H时,合成得到4a,总收率60%。但当R=Me时,虽尝试用多种刘易斯酸作为催化剂,但Michael加成反应的产率没有明显提高,仅为18%。当R=Et时,则没有得到对应的Michae1加成反应产物。因此,此路线适用于合成羰基a-H没有被取代的螺环化合物(Scheme1)。
路线二：先由硝基甲烷对N-Boc-4-哌啶酮进行亲核加成和消去反应生成α，β-不饱和硝基化合物12,继而通过Michael加成反应引入α-取代的酯基得到化合物13,最后还原硝基并关环得到目标产品14。此方法适用于芳香环取代羰基a-H的螺环化合物的合成,单步反应收率达到中等及中等以上(Scheme2)。
路线三：先用路线一合成3-羰基-2,8-二氮杂螺[4.5]癸烷4a,再保护酰胺氮得到化合物15,经过螺环羰基α-位的修饰得到化合物16、17、18,最后脱除酰胺氮的保护基得到4-取代-3-羰基-2,8-二氮杂螺[4.5]癸烷类螺环化合物19和20。此路线的关键步骤是羰基α-位的SN2亲核取代反应,一切对亲核取代反应有利的条件都能促进反应进行,提高收率。此路线适用于烷基取代的二氮杂螺环化合物的合成,单步反应收率在中等及中等以上(Scheme3)。
In this thesis,4-substituted tert-butyl3-oxo-2,8-diazaspiro[4.5]decane-8-car-boxylates were synthetized in three different methods using tert-butyl4-oxopiperid-ine-l-carboxylate as starting material. The advantages and disadvantages and application scope of each method were discussed. Sixteen target pruducts have been prepared and characterized by]H NMR、13C NMR、ESI-MS. All of the intermediates identified by'H NMR.
Strategy one:The α,/β-unsaturated esters2a-c were abtained from tert-butyl4-oxopiperidine-l-carboxylate by using Wittig reaction. After undergoing Michael addition, reduction, and cyclization the desired diazaspiro compounds4a-b were obtained. The key step of this method was Michael addition reaction of the nitromethane, when R=H, the yield of4a was60%. When R=Me, the yield of the Michael addition did not increase obviously (only18%) although a variety of Lewis acids were used as catalyst. When R=Et, the corresponding Michael addition reaction product was not found. Therefore, this route could only be used to synthsize the spiro compounds which have no substituted groups (Scheme1).
Strategy two:The α,β-unsaturated nitro compound12was generated from tert-butyl4-oxopiperidine-l-carboxylate1by using nucleophilic addition reaction and elimination reaction. Then a-substituted ester was introduced in by Michael addition reaction. After reduction of nitro and cyclization, the target products were obtained in moderate to good yields. This method could be applied to provide the derisved products which have the aromatic substituted group (Scheme2).
Strategy three:Compound4a was firstly obtained by using strategy one, then protecting the amide nitrogen, modifying the a-site of carbonyl and removing the protecting group,4-substituted tert-butyl3-oxo-2,8-diazaspiro[4.5]decane-8-carbox-ylates19-20were produced. The key step of this route was the SN2reaction. This route was applicable to provide the4-alkyl diazaspiro compouds in moderate to good yields (Scheme3).
引文
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