Direct Selective Oxidative Cross-Coupling of Simple Alkanes with Heteroarenes
Direct Selective Oxidative Cross-Coupling of Simple Alkanes with Heteroarenes
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DOI：
10.1002/anie.201209584
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发表时间：
2013-01-01
影响因子：
16.6
通讯作者：
Burgmann, Lars
中科院分区：
文献类型：
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作者：
Antonchick, Andrey P.;Burgmann, Lars
脂肪族CÀH键在有机化合物中普遍存在，是最不活泼的键之一。直接和选择性的烷烃功能化方法是化学领域一个重要的和长期的目标通过区分CÀH键来实现选择性仍然是一个挑战。在过去的几十年里，Csp3ÀH键氧化功能化形成碳杂原子键的研究取得了巨大的进展。[2,3]通过交叉偶联将CÀH键直接转化为CÀC键，可以最有效地合成产物。[4,5]从两个不同的CÀH键生成Csp3ÀC键的已知直接方法是基于使用氧化试剂和金属催化剂这些方法通常需要高温，过量的试剂，并且仅限于环烷烃。迫切需要开发Csp3ÀH键功能化的有效方法。本文报道了在温和的反应条件下，简单烷烃与杂芳香化合物通过交叉脱氢偶联（CDC）选择性形成Csp3À C键。这种方法允许在环境温度下，在较弱的CÀH键存在的情况下，选择性地功能化较强的Csp3ÀH键。作为我们对CÀH功能化研究的延续，我们重点研究了用简单烷烃制备CDC的方法。我们通过评价4,7 -二氯喹啉（1a）与环己烷（2a；表1）直接烷基化的各种条件开始了我们的研究。[8,9]令我们高兴的是，我们发现杂芳烃1a与简单烷烃2a直接烷基化后的产物3a可以在无过渡金属和温和的环境温度下得到。以苯为溶剂，在[双（三氟乙酰氧基）碘]苯（PIFA）和NaN3存在下，产品3a的产率为46%（表1，条目1）。PIFA和NaN3对于产物3a的形成都是必不可少的；在没有它们的情况下，没有检测到产品3a。在其他实验中，测试了各种溶剂（表1，条目1 - 7；另见辅助信息）。极性溶剂的使用降低了3a的收率。以二氯甲烷和1,2 -二氯乙烷为溶剂，三氯甲烷的去除率分别为72%和67%。然后，筛选各种氧化剂（表1，条目8-13；另见支持信息）。使用[双（三氟乙氧基）碘]五氟苯或PhI (OH) OTs代替PIFA可获得产品3a，但产率较低随后，对各种添加剂进行了测试（表1，条目14-16；另见辅助信息）。虽然其他添加剂都不成功，但当使用无金属的叠氮化物来源时，如三甲基硅基叠氮化物（表1，条目14），可以获得所需的产品3a。最后，当使用增加的环己烷量（10当量）时，3a的分离率为85%（表1，条目17；另见辅助信息）。进一步增加环己烷的用量，以及PIFA和NaN3用量的变化，对3a的产率没有显著影响。因此，对于
Aliphatic CÀH bonds are ubiquitous in organic compounds and are among the least reactive bonds. Direct and selective methods of alkane functionalization are an important and longstanding goal in chemistry.[1] Achieving selectivity by discriminating between CÀH bonds remains a challenge. Over the past decades, enormous progress has been reported for oxidative functionalization of Csp3ÀH bonds to form carbon–heteroatom bonds.[2, 3] The direct conversion of CÀH bonds into CÀC bonds by cross-coupling allows for the most efficient synthesis of products.[4, 5] Known direct methods of Csp3ÀC bond generation from two different CÀH bonds are based on the use of an oxidizing reagent and a metal catalyst.[6] These methods typically require high temperature, an excess of reagents, and are limited to cycloalkanes. The development of efficient methods of Csp3ÀH bond functionalization is highly desired. Herein, we report on the selective formation of Csp3À C bonds by cross-dehydrogenative coupling (CDC) of simple alkanes with heteroaromatic compounds using mild reaction conditions. This method allows for the selective functionalization of stronger Csp3ÀH bonds in the presence of weaker CÀH bonds at ambient temperature. As a continuation of our studies [7] on CÀH functionalization, we focused on the development of methods for CDC with simple alkanes. We began our studies by evaluating various conditions for the direct alkylation of 4, 7-dichloroquinoline (1a) with cyclohexane (2a; Table 1).[8, 9] To our delight, we found that product 3a, resulting from the direct alkylation of heteroarene 1a with simple alkane 2a, can be obtained under transition-metal-free and mild conditions at ambient temperature. Product 3a was obtained with a yield of 46% in presence of [bis (trifluoroacetoxy) iodo] benzene (PIFA) and NaN3 using benzene as the solvent (Table1, entry1). Both PIFA and NaN3 were essential for the formation of product 3a; in their absence, product 3a was not detected. In additional experiments, various solvents were tested (Table 1, entries 1–7; see also the Supporting information). The use of polar solvents led to lower yields of 3a. The best results, 72% and 67% of 3a, were obtained using dichloromethane and 1, 2-dichloroethane, respectively, as solvents. Afterwards, various oxidants were screened (Table 1, entries 8–13; see also the Supporting information). The use of [bis (trifluoroacetoxy) iodo] pentafluorobenzene or PhI (OH) OTs instead of PIFA provided access to product 3a, but with lower yields.[10] Subsequently, various additives were tested (Table 1, entries 14–16; see also the Supporting information). Whereas other additives were unsuccessful, the desired product 3a was obtained when using a metal-free source of azide, such as trimethylsilyl azide (Table1, entry14). Finally, when using an increased loading of cyclohexane (10 equiv), 3a was isolated with a yield of 85%(Table1, entry17; see also the Supporting information). Further increases in the amount of cyclohexane, and variations in the amounts of PIFA and NaN3 did not lead to significant difference in the yield of 3a. Therefore, for the