Weak Coordination as a Powerful Means for Developing Broadly Useful C鈥揌 Functionalization Reactions
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- 作者：Keary M. Engle ; Tian-Sheng Mei ; Masayuki Wasa ; Jin-Quan Yu
- 刊名：Accounts of Chemical Research
- 出版年：2012
- 出版时间：June 19, 2012
- 年：2012
- 卷：45
- 期：6
- 页码：788-802
- 全文大小：1577K
- 年卷期：v.45,no.6(June 19, 2012)
- ISSN：1520-4898
文摘
Reactions that convert carbon鈥揾ydrogen (C鈥揌) bonds into carbon鈥揷arbon (C鈥揅) or carbon鈥揾eteroatom (C鈥揧) bonds are attractive tools for organic chemists, potentially expediting the synthesis of target molecules through new disconnections in retrosynthetic analysis. Despite extensive inorganic and organometallic study of the insertion of homogeneous metal species into unactivated C鈥揌 bonds, practical applications of this technology in organic chemistry are still rare. Only in the past decade have metal-catalyzed C鈥揌 functionalization reactions become more widely utilized in organic synthesis.
Research in the area of homogeneous transition metal鈥揷atalyzed C鈥揌 functionalization can be broadly grouped into two subfields. They reflect different approaches and goals and thus have different challenges and opportunities. One approach involves reactions of completely unfunctionalized aromatic and aliphatic hydrocarbons, which we refer to as 鈥渇irst functionalization鈥? Here the substrates are nonpolar and hydrophobic and thus interact very weakly with polar metal species. To overcome this weak affinity and drive metal-mediated C鈥揌 cleavage, chemists often use hydrocarbon substrates in large excess (for example, as solvent). Because highly reactive metal species are needed in first functionalization, controlling the chemoselectivity to avoid overfunctionalization is often difficult. Additionally, because both substrates and products are comparatively low-value chemicals, developing cost-effective catalysts with exceptionally high turnover numbers that are competitive with alternatives (including heterogeneous catalysts) is challenging. Although an exciting field, first functionalization is beyond the scope of this Account.
The second subfield of C鈥揌 functionalization involves substrates containing one or more pre-existing functional groups, termed 鈥渇urther functionalization鈥? One advantage of this approach is that the existing functional group (or groups) can be used to chelate the metal catalyst and position it for selective C鈥揌 cleavage. Precoordination can overcome the paraffin nature of C鈥揌 bonds by increasing the effective concentration of the substrate so that it need not be used as solvent. From a synthetic perspective, it is desirable to use a functional group that is an intrinsic part of the substrate so that extra steps for installation and removal of an external directing group can be avoided. In this way, dramatic increases in molecular complexity can be accomplished in a single stroke through stereo- and site-selective introduction of a new functional group. Although reactivity is a major challenge (as with first functionalization), the philosophy in further functionalization differs; the major challenge is developing reactions that work with predictable selectivity in intricately functionalized contexts on commonly occurring structural motifs.
In this Account, we focus on an emergent theme within the further functionalization literature: the use of commonly occurring functional groups to direct C鈥揌 cleavage through weak coordination. We discuss our motivation for studying Pd-catalyzed C鈥揌 functionalization assisted by weakly coordinating functional groups and chronicle our endeavors to bring reactions of this type to fruition. Through this approach, we have developed reactions with a diverse range of substrates and coupling partners, with the broad scope likely stemming from the high reactivity of the cyclopalladated intermediates, which are held together through weak interactions.
Research in the area of homogeneous transition metal鈥揷atalyzed C鈥揌 functionalization can be broadly grouped into two subfields. They reflect different approaches and goals and thus have different challenges and opportunities. One approach involves reactions of completely unfunctionalized aromatic and aliphatic hydrocarbons, which we refer to as 鈥渇irst functionalization鈥? Here the substrates are nonpolar and hydrophobic and thus interact very weakly with polar metal species. To overcome this weak affinity and drive metal-mediated C鈥揌 cleavage, chemists often use hydrocarbon substrates in large excess (for example, as solvent). Because highly reactive metal species are needed in first functionalization, controlling the chemoselectivity to avoid overfunctionalization is often difficult. Additionally, because both substrates and products are comparatively low-value chemicals, developing cost-effective catalysts with exceptionally high turnover numbers that are competitive with alternatives (including heterogeneous catalysts) is challenging. Although an exciting field, first functionalization is beyond the scope of this Account.
The second subfield of C鈥揌 functionalization involves substrates containing one or more pre-existing functional groups, termed 鈥渇urther functionalization鈥? One advantage of this approach is that the existing functional group (or groups) can be used to chelate the metal catalyst and position it for selective C鈥揌 cleavage. Precoordination can overcome the paraffin nature of C鈥揌 bonds by increasing the effective concentration of the substrate so that it need not be used as solvent. From a synthetic perspective, it is desirable to use a functional group that is an intrinsic part of the substrate so that extra steps for installation and removal of an external directing group can be avoided. In this way, dramatic increases in molecular complexity can be accomplished in a single stroke through stereo- and site-selective introduction of a new functional group. Although reactivity is a major challenge (as with first functionalization), the philosophy in further functionalization differs; the major challenge is developing reactions that work with predictable selectivity in intricately functionalized contexts on commonly occurring structural motifs.
In this Account, we focus on an emergent theme within the further functionalization literature: the use of commonly occurring functional groups to direct C鈥揌 cleavage through weak coordination. We discuss our motivation for studying Pd-catalyzed C鈥揌 functionalization assisted by weakly coordinating functional groups and chronicle our endeavors to bring reactions of this type to fruition. Through this approach, we have developed reactions with a diverse range of substrates and coupling partners, with the broad scope likely stemming from the high reactivity of the cyclopalladated intermediates, which are held together through weak interactions.