Direct cyanation of heteroaromatic compounds mediated by hypervalent iodine(III) reagents: In situ generation of PhI(III)-CN species and their cyano transfer
Direct cyanation of heteroaromatic compounds mediated by hypervalent iodine(III) reagents: In situ generation of PhI(III)-CN species and their cyano transfer
复制标题
DOI：
10.1021/jo061820i
复制
发表时间：
2007-01-05
影响因子：
3.6
通讯作者：
Kita, Yasuyuki
中科院分区：
文献类型：
--
作者：
Dohi, Toshifumi;Morimoto, Koji;Kita, Yasuyuki
[图片]高价碘（III）试剂在温和条件下（环境温度）介导多种富电子杂芳香化合物（如吡咯1、噻吩3和吲哚5）的直接氰化反应，而不需要任何预官能化。市售的三甲基硅氰可用作稳定有效的氰源，反应在均相体系中进行。吡咯的n取代基是避免氧化双吡咯偶联过程的关键，因此在室温下，利用苯基吡啶双（三氟乙酸酯）（PIFA）、TMSCN和BF3中心点Et2O的组合，选择性地在n - tosylpyroroles 1的2位上引入氰基，收率较高。在反应机理中，杂芳香化合物的阳离子自由基中间体是单电子氧化的结果，而成功转化的关键似乎取决于所使用底物的氧化电位。因此，该反应也成功地扩展到具有类似于n -甲基吡咯氧化电位的其他杂芳香族化合物，如噻吩3和吲哚5。然而，在N-tosylindole 5a的情况下，从2-和3-位置得到的反应产物的区域异构体混合物。在我们实验室进行的进一步调查提供了在反应过程中真正的活性碘（III）物种的见解；该反应是由PIFA中三氟乙酰氧基与TMSCN在碘（III）中心的配体交换反应生成的具有氰基原位配体的活性高价碘（III）诱导的，并且通过高价碘(III)-氰基中间体的高氰基转移能力实现了对杂芳烃化合物的有效氰基引入。事实上，在没有TMSCN的情况下，n - tosylpyrorole 1a与高价碘(III)-氰基化合物（如（二氰）碘苯8）发生反应，可以获得高产率的2-氰化产物2a，有效制备中间体对于成功转化至关重要。1,3,5,7- tetrakis[4-{双（三氟乙酰氧基）碘}苯基]adamantane 12是一种可回收的高价碘（III）试剂，在氰化反应中也可与PIFA相媲美，作为一种有价值的替代品，通过简单的检测分离氰化产物，可提供高产量的杂芳香氰化物。因此，将可回收试剂12、TMSCN和BF3中心点Et2O在二氯甲烷中预混30 min制备活性高价碘(III)-CN后，多种吡咯1和噻吩3反应得到所需的高收率氰化产物2和4。将反应溶剂替换为甲醇后，通过过滤回收的碘化合物13可以重复使用而不损失活性（氧化剂12可以通过m-CPBA对13进行再氧化得到）。
[GRAPHICS]Hypervalent iodine(III) reagents mediate the direct cyanating reaction of a wide range of electron-rich heteroaromatic compounds such as pyrroles 1, thiophenes 3, and indoles 5 under mild conditions (ambient temperature), without the need for any prefunctionalization. Commercially available trimethylsilylcyanide is usable as a stable and effective cyanide source, and the reaction proceeds in a homogeneous system. The N-substituent of pyrroles is crucial to avoid the undesired oxidative bipyrrole coupling process, and thus a cyano group was introduced selectively at the 2-position of N-tosylpyrroles 1 in good yields using the combination of phenyliodine bis(trifluoroacetate) (PIFA), TMSCN, and BF3 center dot Et2O at room temperature. In the reaction mechanism, cation radical intermediates of heteroaromatic compounds are involved as a result of single electron oxidation, and the key to successful transformations seems to depend on the oxidation potential of the substrates used. Thus, the reaction was also successfully extended to other heteroaromatic compounds having oxidation potentials similar to that of N-tosylpyrroles such as thiophenes 3 and indoles 5. However, regioisomeric mixtures of the products derived from the reaction at the 2- and 3-positions were obtained in the case of N-tosylindole 5a. Further investigation performed in our laboratory provided insights into the real active iodine(III) species during the reaction; the reaction is induced by an active hypervalent iodine(III) species having a cyano ligand in situ generated by ligand exchange reaction at the iodine(III) center between trifluoroacetoxy group in PIFA and TMSCN, and effective cyanide introduction into heteroaromatic compounds is achieved by means of the high cyano transfer ability of the hypervalent iodine(III)-cyano intermediates. In fact, the reaction of N-tosylpyrrole 1a with a hypervalent iodine(III)-cyano compound (e.g., (dicyano)iodobenzene 8), in the absence of TMSCN, took place to afford the 2-cyanated product 2a in good yield, and an effective preparation of the intermediates is of importance for successful transformation. 1,3,5,7-Tetrakis[4-{bis(trifluoroacetoxy)iodo}phenyl]adamantane 12, a recyclable hypervalent iodine(III) reagent, was also comparable in the cyanating reactions as a valuable alternative to PIFA, affording a high yield of the heteroaromatic cyanide by facilitating isolation of the cyanated products with a simple workup. Accordingly, after preparing the active hypervalent iodine(III)-CN species by premixing of a recyclable reagent 12, TMSCN, and BF3 center dot Et2O for 30 min in dichloromethane, reaction of a variety of pyrroles 1 and thiophenes 3 provided the desired cyanated products 2 and 4 in high yields. The iodine compound 13, recovered by filtration after replacement of the reaction solvent to MeOH, could be reused without any loss of activity (the oxidant 12 can be obtained nearly quantitatively by reoxidation of 13 using m-CPBA).