A General and Mild Palladium-Catalyzed Domino Reaction for the Synthesis of 2H-Indazoles
A General and Mild Palladium-Catalyzed Domino Reaction for the Synthesis of 2H-Indazoles
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DOI：
10.1002/anie.200902323
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发表时间：
2009-01-01
影响因子：
16.6
通讯作者：
Lindenschmidt, Andreas
中科院分区：
文献类型：
--
作者：
Halland, Nis;Nazare, Marc;Lindenschmidt, Andreas
吲唑类化合物在药物发现中发挥着越来越重要的作用。它们作为优势结构如吲哚和苯并咪唑的有效电子等排体。此外，这种重要的支架能够与各种不同的靶标相互作用，正如越来越多的生物活性吲唑衍生物的报道所强调的那样。[1]然而，目前只有有限数量的方法用于区域选择性合成N-取代的吲唑。大多数方法提供了在化学上有利的1H-吲唑或1H-和2 H-吲唑的混合物，而2 H-吲唑的区域选择性形成仍然是一个非常具有挑战性的任务。缺乏直接、有效和区域选择性的合成方法来构建2 H-吲唑，阻碍了它们在例如药物化学中的更广泛应用。[2]因此，对于开发由容易获得的前体简单且通用地合成2 H-吲唑的需求尚未得到满足。在此，我们报告了一个简单的多米诺反应序列，包括单取代肼2与2-卤代苯基乙炔1的区域选择性偶联，然后通过5-外-dig环化进行分子内氢胺化，随后环外双键异构化，得到芳香族2 H-吲哚（方案1）。[3]该策略中的第一个挑战是开发单取代肼2与2-卤代苯基乙炔1的区域选择性过渡金属催化偶联以提供所需的N，N '-二取代肼4。虽然已知许多过渡金属催化的芳基卤化物与酰胺、胺、酰肼和腙的偶联反应，但只有少数肼的偶联反应被报道[4]，并且所报道的用于形成N，N-二芳基肼的肼偶联反应中只有一种是区域选择性的。[4d]在开发我们提出的策略中的第二个挑战是控制氢胺化/环化步骤以形成1，2-二氢吲唑5，因为其他可能的环化途径导致其他产物，例如1，2-二氢噌啉和N-氮杂吲哚。[5]二氢-2H-吲唑5中的环外双键异构化生成芳族2 H-吲唑3预期在反应条件下自发发生，因此不会造成任何问题。N '-二芳基肼4.在优化反应参数（过渡金属、金属盐、配体、碱、溶剂和温度）后，发现当催化剂体系[Pd 2（dba）3]/PtBu 3（1：2）在甲苯中在808 ℃下使用NaOtBu作为碱（dba=二亚苄基丙酮）时，所需的偶联在短短几小时内干净地进行，并且具有完全的区域选择性。据我们所知，该反应是第一个区域选择性过渡金属催化的单取代肼偶联反应，得到N，N ′-二取代肼产物。[6]我们进一步优化了反应参数，以确定促进1a与2a的完全多米诺反应作为一锅反应的条件（表1）。[7]我们发现使用极性溶剂如DMF、NMP或DMA与Cs2 CO 3的组合导致以良好产率形成所需的2 H-吲唑3a（表1，条目2-4），而
Indazoles play an increasingly important role in drug discovery. They act as an efficient isostere for privileged structures such as indoles and benzimidazoles. Furthermore, this important scaffold is able to interact with a variety of diverse targets, as highlighted by the growing number of reports of biologically active indazole derivatives.[1] However, only a limited number of approaches for the regioselective synthesis of N-substituted indazoles are available today. Most approaches afford the thermodynamically favored 1H-indazole or mixtures of 1H-and 2H-indazoles, whereas the regioselective formation of 2H-indazoles remains a very challenging task. The lack of a direct, efficient, and regioselective synthetic procedure for the construction of 2H-indazoles prevents their broader application in, for example, medicinal chemistry.[2] Thus, there is an unmet need for the development of a simple and general synthesis of 2H-indazoles from readily available precursors. Herein we report a straightforward domino reaction sequence consisting of a regioselective coupling of monosubstituted hydrazines 2 with 2-halophenylacetylenes 1, followed by an intramolecular hydroamination through a 5-exo-dig cyclization and subsequent isomerization of the exocyclic double bond to give the aromatic 2H-indazole (Scheme 1).[3] The first challenge in this strategy was the development of a regioselective transition-metal-catalyzed coupling of monosubstituted hydrazines 2 with 2-halophenylacetylenes 1 to afford the required N, N’-disubstituted hydrazines 4. Although a number of transition-metal-catalyzed coupling reactions of aryl halides with amides, amines, hydrazides, and hydrazones are known, only a few coupling reactions of hydrazines have been reported,[4] and only one of the reported hydrazine couplings, for the formation of N, N-diaryl hydrazines, is regioselective.[4d] A second challenge in the development of our proposed strategy was the control of the hydroamination/cyclization step to form the 1, 2-dihydroindazole 5, as other possible cyclization pathways lead to other products, such as 1, 2-dihydrocinnolines and N-azaindoles.[5] The isomerization of the exocyclic double bond in dihydro-2H-indazole 5 to give the aromatic 2H-indazole 3 was expected to occur spontaneously under the reaction conditions and thus not to pose any problems.We initiated our investigation by screening for reaction conditions under which the coupling of 1-chloro-2-phenylethynylbenzene (1a) and phenylhydrazine (2a) would proceed efficiently to give the N, N’-diaryl hydrazine 4. Upon optimization of the reaction parameters (the transition metal, metal salt, ligand, base, solvent, and temperature), the desired coupling was found to proceed cleanly within just a few hours and with complete regioselectivity when the catalyst system [Pd2 (dba) 3]/PtBu3 (1: 2) was used in toluene at 808C with NaOtBu as the base (dba= dibenzylideneacetone). This reaction is to our knowledge the first regioselective transition-metal-catalyzed coupling of monosubstituted hydrazines to give N, N’-disubstituted hydrazine products.[6] We further optimized the reaction parameters to identify conditions that would promote the complete domino reaction of 1a with 2a as a one-pot reaction (Table 1).[7] We found that the use of polar solvents, such as DMF, NMP, or DMA, in combination with Cs2CO3 led to the formation of the desired 2H-indazole 3a in good yield (Table 1, entries 2–4), whereas