Synthesis of Isoquinolines and Pyridines via Palladium-Catalyzed Iminoannulation of Internal Acetylenes
Synthesis of Isoquinolines and Pyridines via Palladium-Catalyzed Iminoannulation of Internal Acetylenes
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DOI：
10.1021/jo980871f
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发表时间：
1998-07
影响因子：
3.6
通讯作者：
K. R. Roesch;R. Larock
中科院分区：
文献类型：
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作者：
K. R. Roesch;R. Larock
环化过程在有机合成中有许多应用，主要是由于可以容易地快速构建各种复杂的杂环和碳环。1在我们自己的实验室中，已经证明钯催化的成环方法可以有效地用于吲哚，2苯并呋喃，3异香豆素，3茚酮，4和多环芳烃的合成。5取代的异喹啉先前已经通过使用钯方法合成。例如，Pfeffer报道了由环钯化的N，N-二甲基苄胺络合物形成二取代的异喹啉衍生物，6 Heck观察到通过环钯化的N-叔丁基苯甲醛亚胺四氟硼酸盐与二苯基乙炔反应以22%的产率形成3，4-二苯基异喹啉。7 Widdowson还报道了基于环钯化的N-叔丁基芳基醛亚胺的异喹啉合成。8然而，这些实施例的主要缺点是它们相对于钯是化学计量的，并且在后一种合成中，最后的热解步骤极大地限制了合成效用。我们对这些类型的成环反应的兴趣促使我们研究这些异喹啉合成的催化形式。我们现在报道，钯催化的内炔的亚氨基成环反应很容易得到各种各样的氮杂环，包括异喹啉，四氢异喹啉，吡啶和吡啶。我们的初步结果总结在表1中。我们的初步研究集中在钯催化的环内炔采用甲基亚胺邻碘苯甲醛。然而，即使在升高的温度下，该底物也不能产生任何所需的异喹啉。此外，使用相应的异丙基、烯丙基和苄基亚胺也没有得到所需的杂环产物。R-甲基苄基亚胺与二苯基乙炔的反应确实产生了所需产物3，4-二苯基异喹啉，尽管产率低（6-11%）。然而，通过使用叔丁基亚胺，在优化反应条件（等式1）之后，我们用各种炔获得了显著改进的结果。2-5叔丁基亚胺与2当量炔在5mol%Pd（OAc）2、10mol%PPh3和1当量Na 2CO 3存在下在作为溶剂的DMF中在100 ℃下反应，在短的反应时间内以良好至优异的产率得到所需的杂环产物。各种芳基取代的炔通过邻碘苯甲醛（1）的叔丁基亚胺的环化以中等至优异的产率和高区域选择性提供所需的二取代异喹啉杂环（表1，条目1-4）。产物的区域化学是基于与我们以前的炔成环化学2 -5的类比以及化合物36和49的光谱和物理数据与文献中已有的那些的比较。相对无阻碍的二炔和烯炔通过亚胺1的环化也以良好的产率得到预期的异喹啉产物，尽管得到区域异构体的混合物（表1，条目5和6）。这是有趣的，因为产物2-5都作为单一区域异构体分离。此外，二炔成环得到在4-位带有更多受阻苯基的意外主要产物（表1，条目5）。有趣的是，许多烷基取代的炔，即4-辛炔，3-己炔，4，4-二甲基炔，...
Annulation processes have found numerous applications in organic synthesis, primarily due to the ease with which a wide variety of complicated hetero-and carbocycles can be rapidly constructed. 1 In our own laboratories, it has been demonstrated that palladium-catalyzed annulation methodology can be effectively employed for the synthesis of indoles, 2 benzofurans, 3 isocoumarins, 3 indenones, 4 and polycyclic aromatic hydrocarbons. 5 Substituted isoquinolines have previously been synthesized by employing palladium methodology. For instance, Pfeffer reported the formation of a disubstituted isoquinoline derivative from a cyclopalladated N, N-dimethylbenzylamine complex, 6 and Heck observed the formation of 3, 4-diphenylisoquinoline in 22% yield by the reaction of cyclopalladated N-tert-butylbenzaldimine tetrafluoroborate with diphenylacetylene. 7 Widdowson has also reported an isoquinoline synthesis based on cyclopalladated N-tert-butylarylaldimines. 8 These examples, however, suffer the major disadvantage that they are stoichiometric with respect to palladium, and in the latter synthesis, a final pyrolysis step greatly limits the synthetic utility. Our own interest in these types of annulation reactions has prompted us to investigate a catalytic version of these isoquinoline syntheses. We now report that the palladiumcatalyzed iminoannulation of internal alkynes readily affords a wide variety of nitrogen heterocycles, including isoquinolines, tetrahydroisoquinolines, pyrindines, and pyridines. Our preliminary results are summarized in Table 1. Our initial studies focused on the palladium-catalyzed annulation of internal alkynes employing the methyl imine of o-iodobenzaldehyde. However, this substrate failed to produce any of the desired isoquinoline even at elevated temperatures. Furthermore, use of the corresponding isopropyl, allyl, and benzyl imines also afforded none of the desired heterocyclic products. The reaction of the R-methylbenzyl imine with diphenylacetylene did produce the desired product, 3, 4-diphenylisoquinoline, albeit in low yields (6-11%). By employing the tert-butylimine, however, we obtained substantially improved results with a variety of alkynes, after optimization of the reaction conditions (eq 1).The reaction conditions employed in the present heterocycle synthesis are similar to those that we previously reported for the annulation of alkynes. 2-5 The reaction of the tert-butylimines with 2 equiv of an alkyne in the presence of 5 mol% Pd (OAc) 2, 10 mol% PPh3, and 1 equiv of Na2CO3 in DMF as the solvent at 100 C affords the desired heterocyclic products in good to excellent yields in short reaction times. The annulation of a variety of aryl-substituted alkynes by the tert-butylimine of o-iodobenzaldehyde (1) affords the desired disubstituted isoquinoline heterocycles in moderate to excellent yields with high regioselectivity (Table 1, entries 1-4). The regiochemistry of the products is based on analogy with our previous alkyne annulation chemistry2-5 and comparison of the spectral and physical data for compounds 36 and 49 with those already in the literature. The annulation of a relatively unhindered diyne and enyne by imine 1 also affords the anticipated isoquinoline products in good yields, although mixtures of regioisomers are obtained (Table 1, entries 5 and 6). This is interesting due to the fact that the products 2-5 are all isolated as single regioisomers. In addition, the diyne annulation gives an unexpected major product bearing the more hindered phenyl group in the 4-position (Table 1, entry 5). It is interesting to note that the attempted annulation of many alkyl-substituted alkynes, namely 4-octyne, 3-hexyne, 4, 4-dimethyl …