Use of a Readily Removable Auxiliary Group for the Synthesis of Pyrrolidones by the Palladium-Catalyzed Intramolecular Amination of Unactivated γ C(sp3)-H Bonds
Use of a Readily Removable Auxiliary Group for the Synthesis of Pyrrolidones by the Palladium-Catalyzed Intramolecular Amination of Unactivated γ C(sp3)-H Bonds
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DOI：
10.1002/anie.201305615
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发表时间：
2013-10-11
影响因子：
16.6
通讯作者：
Chen, Gong
中科院分区：
文献类型：
--
作者：
He, Gang;Zhang, Shu-Yu;Chen, Gong
中型内酰胺是天然产物和药物制剂中重要的结构基序。[1]虽然分子内酰胺偶联反应已常规用于内酰胺化，但这些方法需要含有游离氨基和羧酸官能团的底物，并且通常需要额外的保护/脱保护操作。相比之下，基于C13 H键的分子内胺化的策略可以提供从容易获得的酰胺前体得到内酰胺产物的直接方法，从而简化底物制备并实现新的逆合成规划（方案1A）。[2-7]在2008年的开创性报告中，Wasa和Yu公开了他们通过钯催化的N-甲氧基异羟肟酸的邻位C（sp2）NH键的分子内胺化合成g-和d-苯并-稠合内酰胺[Eq. (1)，方案1B]。[8]然而，通过脂肪族底物的未活化的C（sp3）NH键的金属催化胺化合成取代的吡咯烷酮尚未被描述。在此，我们报告了一种有效的和容易适用的方法，用于合成复杂的吡咯烷酮的基础上的钯催化的羧酰胺导向的分子内胺化的未活化的g C（sp3）-OH键（方案1C）。在2012年，Nadres和Daugulis以及我们的研究小组报道了一组钯催化的、吡啶酰胺导向的和PhI（OAc）2介导的胺底物的未活化的C（sp3）NH和C（sp2）NH键的分子内胺化反应，以形成氮杂环丁烷、吡咯烷和吲哚啉[Eq. (2)方案1; PA=吡啶酰胺]。[9-11]受到这一成功的鼓舞，我们继续探索衍生自羧酸的仲酰胺底物是否可以在钯催化下经历类似的转化以形成中等大小的内酰胺。我们以8-氨基喹啉偶联的丙氨酸甲酰胺5开始研究，希望形成b-内酰胺产物7 [Eq. (3)，方案2]。8-氨基喹啉（AQ）基团，首先由Daugulis研究小组引入，[12]已经在许多b-CNOH官能化反应中表现出优异的能力。[13此外，Corey及其同事表明，在钯催化下，N-邻苯二甲酰基保护的和AQ偶联的氨基酸底物的B C（sp3）OH键可以容易地用ArI以良好的产率芳基化。[13 a]与3瓦尔的容易的PA-导向环化形成氮杂环丁烷4相反，在类似条件下，在PhI（OAc）2存在下，用钯催化剂进行的AQ-偶联的5的反应不能得到任何b-内酰胺产物7，并且仅提供痕量的乙酰氧基化副产物8。在5上进行的氘交换实验显示，其B C1 H2键在类似条件下在钯催化剂存在下但没有PhI（OAc）2 [Eq. (4)，方案2]。与在608 ℃下在类似的钯催化下5的B C（sp3）OH键与ArI的容易偶联[12 B]相比，即使在1108 ℃下，用PhI（OAc）2氧化可能相同的五元PdII钯配合物中间体6以形成PdIV也令人惊讶地困难。[15]四元内酰胺中固有的环张力也可能不利于所需产物的形成。相比之下，环张力不会阻碍g C（sp3）-OH键胺化形成吡咯烷酮。虽然它在动力学上不太受欢迎，但我们希望它是一个六-
Medium-sized lactams are important structural motifs in natural products and pharmaceutical agents.[1] Although intramolecular amide-coupling reactions have been routinely used for lactamization, these methods require substrates that contain both free amino and carboxylic acid functional groups and often require additional protection/deprotection operations. In contrast, a strategy based on the intramolecular amination of CĀH bonds could provide a straightforward approach to lactam products from readily available amide precursors and thus simplify substrate preparation and enable novel retrosynthetic planning (Scheme 1A).[2–7] In a seminal report in 2008, Wasa and Yu disclosed their synthesis of g-and d-benzo-fused lactams through the palladium-catalyzed intramolecular amination of ortho C (sp2) ĀH bonds of N-methoxyhydroxamic acids [Eq.(1), Scheme1B].[8] However, the synthesis of substituted pyrrolidinones by the metal-catalyzed amination of unactivated C (sp3) ĀH bonds of aliphatic substrates has not yet been described. Herein, we report an efficient and readily applicable method for the synthesis of complex pyrrolidinones on the basis of the palladiumcatalyzed carboxamide-directed intramolecular amination of unactivated g C (sp3) ĀH bonds (Scheme 1C). In 2012, Nadres and Daugulis as well as our research group reported a set of palladium-catalyzed, picolinamidedirected, and PhI (OAc) 2-mediated intramolecular amination reactions of unactivated C (sp3) ĀH and C (sp2) ĀH bonds of amine substrates to form azetidines, pyrrolidines, and indolines [Eq.(2), Scheme 1; PA= picolinamide].[9–11] Encouraged by this success, we proceeded to explore whether secondary amide substrates derived from carboxylic acids could undergo a similar transformation to form medium-sized lactams under palladium catalysis. We commenced the study with the 8-aminoquinoline-coupled alanine carboxamide 5, in the hope of forming the b-lactam product 7 [Eq.(3), Scheme 2]. The 8-aminoquinoline (AQ) group, first introduced by the Daugulis research group,[12] has demonstrated excellent ability in a number of b-CĀH functionalization reactions.[13, 14] Additionally, Corey and co-workers showed that b C (sp3) ĀH bonds of N-phthaloyl-protected and AQ-coupled amino acid substrates can be readily arylated with ArI in good yield under palladium catalysis.[13a]In contrast to the facile PA-directed cyclization of 3 Val to form azetidine 4, the reaction of AQ-coupled 5 under similar conditions with a palladium catalyst in the presence of PhI (OAc) 2 failed to give any of the b-lactam product 7 and provided only a trace amount of an acetoxylated side product 8. Deuterium-exchange experiments performed on 5 revealed that its b CĀH bonds were readily exchanged under similar conditions in the presence of a palladium catalyst but without PhI (OAc) 2 [Eq.(4), Scheme 2]. As compared with the facile coupling of the b C (sp3) ĀH bonds of 5 with ArI under similar palladium catalysis at 608C,[12b] the oxidation of probably the same five-membered PdII palladacycle intermediate 6 with PhI (OAc) 2 to form PdIV was surprisingly difficult even at 1108C.[15] The ring strain inherent in four-membered blactams might also have disfavored the formation of the desired product. In comparison, ring strain would not hinder the amination of the g C (sp3) ĀH bonds to form pyrrolidones. Although it is kinetically less favored, we hoped that a six-